Compositions and methods of use of cis-4-[2-{[(3s,4r)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9h-purin-9-yl]-1-methylcyclohexane-1-carboxamide

ABSTRACT

Provided are formulations and dosage forms of cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide, alternatively named (1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide, or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

This application is a continuation of U.S. patent application Ser. No.16/845,195, filed Apr. 10, 2020, currently allowed, which is acontinuation of U.S. patent application Ser. No. 16/710,533, filed Dec.11, 2019, now U.S. Pat. No. 10,653,697, issued May 19, 2020, which is acontinuation of U.S. patent application Ser. No. 16/150,350, filed Oct.3, 2018, now U.S. Pat. No. 10,543,214, issued Jan. 28, 2020, whichclaims the benefit of U.S. Provisional Application No. 62/568,107, filedOct. 4, 2017, the entire content of which is incorporated herein byreference.

1. FIELD

Provided are formulations and dosage forms ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,alternatively named(1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof, as well as suchformulations for use in treating, preventing or managing cancer.

2. BACKGROUND

Cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof has been shown to haveanti-cancer activities. Exemplary methods of use are provided in U.S.Pat. No. 9,512,124 and U.S. Patent Publication No. 2017/0281633.Exemplary polymorphs ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideare provided in U.S. Publication No. 2017/0281633.

There is a need for further methods of use and formulations ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof for the treatment of cancer.

3. BRIEF SUMMARY

In certain embodiments, provided herein is a capsule comprising Compound1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide),or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof in an amount that is 30-40%of the capsule by weight, an excipient in an amount that is 50-60% ofthe capsule by weight, and tocophersolan in an amount that is 5-15% ofthe capsule by weight.

In certain embodiments, provided herein is a capsule comprising 60-70%Compound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide),or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 20-30% of anexcipient by weight, and 5-15% of tocophersolan by weight.

In certain embodiments, provided herein is a capsule comprising 45-55%Compound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide),or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 35-45% of anexcipient by weight, and 5-15% of tocophersolan by weight.

In certain embodiments, provided herein is a capsule comprising 45-55%Compound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide),or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, and 45-55% of anexcipient by weight.

In certain embodiments, provided herein is a capsule comprisingcomprises 0.5-3% of a citrate salt of Compound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide)by weight, 10-30% microcrystalline cellulose (e.g., Avicel PH102) byweight, 55-75% mannitol (e.g., Parteck M200) by weight, 0.5-3% sodiumlauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidoneby weight, 0.2-1% fumed silica (e.g., AEROSIL 200) by weight, and 0.5-3%magnesium stearate by weight.

In certain embodiments, provided herein is a capsule comprising 2-12% ofa citrate salt of Compound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide)by weight, 10-30% microcrystalline cellulose (e.g., Avicel PH102) byweight, 50-70% mannitol (e.g., Parteck M200) by weight, 0.5-3% sodiumlauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidoneby weight, 0.2-1% fumed silica (e.g., AEROSIL 200) by weight, and 0.5-3%magnesium stearate by weight.

In certain embodiments, provided herein is a capsule comprising 5-20% ofa citrate salt of Compound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide)by weight, 10-30% microcrystalline cellulose (e.g., Avicel PH102) byweight, 50-70% mannitol (e.g., Parteck M200) by weight, 0.5-3% sodiumlauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidoneby weight, 0.2-1% fumed silica (e.g., AEROSIL 200) by weight, and 0.5-3%magnesium stearate by weight.

In certain embodiments, provided herein is a tablet comprising 15-25% ofCompound 1(cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide)or an isotopologue, pharmaceutically acceptable salt, tautomer, solvate,hydrate, co crystal, clathrate, or polymorph thereof by weight, 32-43%of microcrystalline cellulose (e.g., Avicel PH102) by weight, 32-43% ofmannitol (e.g., EMPROVE Parteck) by weight, 2-6% of croscarmellosesodium (e.g., Ac-Di-Sol) by weight, 0.3-0.7% of fumed silica (e.g.,AEROSIL 200) by weight, and 0.5-1.5% magnesium stearate by weight.

In one embodiment, AEROSIL 200 is a fumed silica with a surface area ofabout 175 to about 225 m²/g (e.g., about 200 m²/g). In one embodiment,Ac-Di-Sol is croscarmellose sodium. In one embodiment, EMPROVE Parteckis mannitol.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a blending process for preparation of formulations ofCompound 1.

FIG. 2 shows dissolution profiles of Study 1 formulations in gelatincapsules under dissolution condition 1 in Table 4.

FIG. 3 shows dissolution profiles of Study 1 formulations in HPMCcapsules under dissolution condition 1 in Table 4.

FIG. 4 shows dissolution profiles of Study 1 formulations in gelatincapsules under dissolution condition 2 in Table 5.

FIG. 5 shows dissolution profiles of Study 1 formulations in HPMCcapsules under dissolution condition 2 in Table 5.

FIG. 6 shows dissolution profiles of Study 2 formulations in gelatincapsules under dissolution condition 1 in Table 4.

FIG. 7 shows dissolution profiles of Study 2 formulations in HPMCcapsules under dissolution condition 1 in Table 4.

FIG. 8 shows dissolution profiles of Study 2 formulations in gelatincapsules under dissolution condition 2 in Table 5.

FIG. 9 shows dissolution profiles of Study 2 formulations in HPMCcapsules under dissolution condition 2 in Table 5.

FIG. 10 shows dissolution profiles of Study 3 formulations in gelatincapsules under dissolution condition 2 in Table 5.

FIG. 11 shows dissolution profiles of Study 4 formulations in gelatincapsules under dissolution condition 3 in Table 8.

FIG. 12 shows the plasma concentration of Compound 1 over a 24 hour postdose time after administration of Formulation F4-1 of Study 4formulations in Table 11.

FIG. 13 shows the plasma concentration of Compound 1 over a 24 hour postdose time after administration of Formulation F4-5 of Study 4formulations in Table 11.

FIG. 14 shows the plasma concentration of Compound 1 over a 24 hour postdose time after administration of Formulation F4-7 of Study 4formulations in Table 11.

FIG. 15 shows the comparison in AUC and C_(max) across FormulationsF4-1, F4-5 and F4-7 of Study 4 formulations in the two pH-controlled doggroups as provided in Table 13.

FIG. 16 shows the dissolution profiles of Formulations F18-1 to F18-6 ofTable 18 with basket rotation speed at 100 RPM and in pH 6.5 FastedState Simulated Intestinal Fluid (FaSSIF) as provided in Table 19.

FIG. 17 shows that Formulations F18-2 and F18-5 containing citric acidand encapsulated in gelatin capsule shells showed capsule brittlenessafter 3 months at 40° C./75% RH and capsule breakage after 1 month at50° C./75% RH.

FIG. 18 shows the release profiles of each formulation in Table 27 in0.1 N HCl.

FIG. 19 shows the release profiles of each formulation in Table 27 in pH4.5 acetate buffer (50 mM).

FIG. 20 shows the release profiles of each formulation in Table 27 in pH6.8 phosphate buffer (50 mM).

FIG. 21 shows the dissolution profiles of the 25 mg enhanced formulation(F27-15, Table 27) with apparatus I at 100 RPM in 0.1N HCl, pH 4.5acetate buffer and pH 6.8 phosphate buffer.

FIG. 22 shows the dissolution profiles of a conventional formulation(F4-1 in Table 11) with apparatus I at 100 RPM in 0.1N HCl, pH 4.5acetate buffer and pH 6.8 phosphate buffer.

FIG. 23 shows high variability in dissolution of enhanced formulation(F27-15, Table 27) with HPMC capsule shells (25 mg strength) at neutralpH.

FIG. 24 shows that no variability was observed in dissolution ofenhanced formulation (F27-15, Table 27) with gelatin capsule shells (25mg strength) at neutral pH.

FIG. 25 shows high variability in dissolution of enhanced formulation(F27-15, Table 27) with HPMC capsule shells (25 mg strength) at neutralpH in the dissolution media with 0.5% SLS.

FIG. 26 shows that no variability was observed in dissolution ofenhanced formulation (F27-15, Table 27) with gelatin capsule shells (25mg strength) at neutral pH in the dissolution media with 0.5% SLS.

FIG. 27 shows that the SLS only formulation (F27-13 in Table 27) behavedsimilarly in HPMC capsule shells in the dissolution media with 0.5% SLSand without 0.5% SLS.

FIG. 28 shows that the SLS only formulation (F27-13 in Table 27) behavedsimilarly in gelatin capsule shells in the dissolution media with 0.5%SLS and without 0.5% SLS.

FIG. 29 shows that the CA+SLS formulation (F27-10 in Table 27) behaveddifferently in HPMC capsule shells in the dissolution media with 0.5%SLS and without 0.5% SLS.

FIG. 30 shows that HPMC capsules retained gel-like and lumpy residualsolids in the basket at the end of dissolution.

FIG. 31 shows that the 600 g trial 1 batch process flow diagram forpreparation of 600 g formulations.

FIG. 32 shows that the 600 g trial 2 batch process flow diagram forpreparation of 600 g formulations.

FIG. 33 shows the batch process flow diagram for the manufacture of the2 kg technical batches.

FIG. 34 shows dissolution profiles of Compound 1 formulations inintestinal buffer dissolution over 90 minutes.

FIG. 35 shows dissolution profiles of Compound 1 formulations inintestinal buffer dissolution and speciation.

FIG. 36 shows a dissolution comparison across the PVA-P formulations(Capsule B, Capsule E, and Capsule H).

FIG. 37 shows a dissolution comparison across the PVP VA64 formulations(Capsule C and Capsule F).

FIG. 38 shows a dissolution comparison across the HPMC formulations(Capsule A, Capsule D, and Capsule G).

FIG. 39 shows the glass transition temperature versus relative humidity.

FIG. 40 shows the reversible and nonversible heat flow of Capsule A andCapsule H at less then 5% relative humidity.

FIG. 41 shows the reversible and nonversible heat flow of Capsule A andCapsule H at 75% relative humidity.

FIG. 42 shows the reversible and nonversible heat flow of Capsule G andCapsule E at less than 5% relative humidity.

FIG. 43 shows the reversible and nonversible heat flow of Capsule G andCapsule E at 75% relative humidity.

FIG. 44 shows the suspension stability of Capsule A in Methocel.

FIG. 45 shows the suspension stability of Capsule H in Methocel.

FIG. 46 shows the suspension stability of Capsule G in Methocel.

FIG. 47 shows the suspension stability of Capsule E in Methocel.

FIG. 48 shows the suspension stability, as visualized by PLM, of CapsuleA in Methocel.

FIG. 49 shows the suspension stability, as visualized by PLM, of CapsuleH in Methocel.

FIG. 50 shows the suspension stability, as visualized by PLM, of CapsuleG in Methocel.

FIG. 51 shows the suspension stability, as visualized by PLM, of CapsuleE in Methocel.

FIG. 52 shows the plasma concentration profile results following asingle oral administration of Capsule G in male CD-1 mice.

FIG. 53 shows the plasma concentration profile results following asingle oral administration of Capsule E in male CD-1 mice.

FIG. 54 shows the plasma concentration profile results following asingle oral administration of Capsule I in male CD-1 mice.

FIG. 55 shows the plasma concentration profile results following asingle oral administration of Capsule J in male CD-1 mice.

FIG. 56 shows a comparison of the concentration profile resultsfollowing a single oral administration of Capsule G, Capsule E, CapsuleI, and Capsule J.

FIG. 57 shows the dissolution of Tablet A, Tablet B, and Tablet C in pH2 phosphate buffer.

FIG. 58 shows the dissolution of Tablet A (middle curve), Tablet B (topcurve), and Tablet C (bottom curve) in pH 5 phosphate buffer and 0.1%sodium laureth sulfate.

FIG. 59 shows that a citrate salt had a better dissolution profilecompared to a freebase monohydrate.

FIG. 60 shows a spray-drying process providing the spray drieddispersion formulation of Compound 1.

5. DETAILED DESCRIPTION 5.1 Definitions

As used herein, the terms “comprising” and “including” can be usedinterchangeably. The terms “comprising” and “including” are to beinterpreted as specifying the presence of the stated features orcomponents as referred to, but does not preclude the presence oraddition of one or more features, or components, or groups thereof.Additionally, the terms “comprising” and “including” are intended toinclude examples encompassed by the term “consisting of”. Consequently,the term “consisting of” can be used in place of the terms “comprising”and “including” to provide for more specific embodiments of theinvention.

The term “consisting of” means that a subject-matter has at least 90%,95%, 97%, 98% or 99% of the stated features or components of which itconsists. In another embodiment the term “consisting of” excludes fromthe scope of any succeeding recitation any other features or components,excepting those that are not essential to the technical effect to beachieved.

As used herein, the term “or” is to be interpreted as an inclusive “or”meaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term Compound 1 refers to“cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide”,alternatively named“(1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide,”having the structure:

and pharmaceutically acceptable salts, tautomers, solvates, hydrates,co-crystals, clathrates, or polymorphs thereof. In certain embodiments,Compound 1 refers tocis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideand pharmaceutically acceptable salts, tautomers, solvates, hydrates,co-crystals, clathrates, or polymorphs thereof. In certain embodiments,Compound 1 refers to a polymorph of(1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide,such as, inter alia, Free Base Forms A-I, Citrate Forms Y and Z, and HClSalt Forms 1-7, as described in U.S. Publication No. 2017/0283418.

As used herein, unless otherwise specified, the term “pharmaceuticallyacceptable salt(s),” includes, but is not limited to, salts of acidic orbasic moieties of Compound 1. Basic moieties are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that can be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds are those that form non-toxicacid addition salts, e.g., salts containing pharmacologically acceptableanions. Suitable organic acids include, but are not limited to, maleic,fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic,tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic,oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic,gluconic, glucaronic, saccharic, isonicotinic, methanesulfonic,ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic(e.g., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate) acids. Suitableinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids.Compounds that include an amine moiety can form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Chemical moieties that are acidic in nature are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts are alkali metal or alkaline earth metal saltsand, particularly, calcium, magnesium, sodium, lithium, zinc, potassium,or iron salts.

As used herein, and unless otherwise specified, the term “solvate” meansa compound provided herein or a salt thereof that further includes astoichiometric or non-stoichiometric amount of solvent bound bynon-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

A “pharmaceutically acceptable excipient,” refers to a substance thataids the administration of an active agent to a subject by for examplemodifying the stability of an active agent or modifying the absorptionby a subject upon administration. A pharmaceutically acceptableexcipient typically has no significant adverse toxicological effect onthe patient. Examples of pharmaceutically acceptable excipients include,for example, water, NaCl (including salt solutions), normal salinesolutions, 2 normal saline, sucrose, glucose, bulking agents, buffers,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, alcohols, oils, gelatins, carbohydrates such as amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. One of skill in the art will recognize thatother pharmaceutical excipients known in the art are useful in thepresent invention and include those listed in for example the Handbookof Pharmaceutical Excipients, Rowe R. C., Shesky P. J., and Quinn M. E.,6^(th) Ed., The Pharmaceutical Press, RPS Publishing (2009). The terms“bulking agent”, and “buffer” are used in accordance with the plain andordinary meaning within the art.

As used herein, and unless otherwise specified, the term “about,” whenused in connection with doses, amounts, or weight percent of ingredientsof a composition or a dosage form, means dose, amount, or weight percentthat is recognized by those of ordinary skill in the art to provide apharmacological effect equivalent to that obtained from the specifieddose, amount, or weight percent is encompassed. Specifically, the term“about” contemplates a dose, amount, or weight percent within 30%, 25%,20%, 15%, 10%, or 5% of the specified dose, amount, or weight percent isencompassed.

As used herein, “administer” or “administration” refers to the act ofphysically delivering a substance as it exists outside the body into asubject. Administration includes all forms known in the art fordelivering therapeutic agents, including but not limited to topical,mucosal, injections, intradermal, intravenous, intramuscular delivery orother method of physical delivery described herein or known in the art(e.g., implantation of a slow-release device, such as a mini-osmoticpump to a subject; liposomal formulations; buccal; sublingual; palatal;gingival; nasal; vaginal; rectal; intra-arteriole; intraperitoneal;intraventricular; intracranial; or transdermal).

An “effective amount” is an amount sufficient to achieve the effect forwhich it is administered (e.g., treat a disease or reduce one or moresymptoms of a disease or condition). Thus, administration of an “amount”of a compound described herein to a subject refers to administration of“an amount effective,” to achieve the desired therapeutic result. A“therapeutically effective amount” of a compound described herein forpurposes herein is thus determined by such considerations as are knownin the art. The term “therapeutically effective amount” of a compositiondescribed herein refers to the amount of the composition that, whenadministered, is sufficient to treat one or more of the symptoms of adisease described herein (e.g., cancer). Administration of a compounddescribed herein can be determined according to factors such as, forexample, the disease state, age, sex, and weight of the individual. Atherapeutically effective amount also refers to any toxic or detrimentaleffects of Compound 1 are outweighed by the therapeutically beneficialeffects. Exemplary diseases to be treated are provided in U.S. Pat. No.9,512,124 and U.S. Patent Publication No. 2017/0281633.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a patient with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease. Exemplary diseases tobe treated are provided in U.S. Pat. No. 9,512,124 and U.S. PatentPublication No. 2017/0281633.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of diseases or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment. Exemplary diseases to be prevented are providedin U.S. Pat. No. 9,512,124 and U.S. Patent Publication No. 2017/0281633.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a patientderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease, or lengthening the time during which the remains in remission.Exemplary diseases to be managed are provided in U.S. Pat. No. 9,512,124and U.S. Patent Publication No. 2017/0281633.

The terms “subject,” “patient,” “subject in need thereof,” and “patientin need thereof” are herein used interchangeably and refer to a livingorganism suffering from one or more of the diseases described herein(e.g., cancer) that can be treated by administration of a compositiondescribed herein. Non-limiting examples of organisms include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In embodiments, a subject ishuman. A human subject can be between the ages of about 1 year old toabout 100 years old. In embodiments, subjects herein can becharacterized by the disease being treated (e.g., a “cancer subject”, ora “solid tumor subject”). Exemplary diseases to be treated are providedin U.S. Pat. No. 9,512,124 and U.S. Patent Publication No. 2017/0281633.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

Finally, in general, the technical teaching of one embodiment can becombined with that disclosed in other embodiments provided herein.

5.2 Compound 1

The compound suitable for use in the methods and formulations providedherein is Compound 1:cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,alternatively named(1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamidehaving the structure:

or its isotopologues, pharmaceutically acceptable salts, tautomers,solvates, hydrates, co-crystals, clathrates, or polymorphs thereof.

Compound 1 can be prepared according to the methods described in theExamples provided herein or as described in U.S. Pat. No. 9,512,124, thedisclosure of which is incorporated herein by reference in its entirety.The compound can be also synthesized according to other methods apparentto those of skill in the art based upon the teaching herein.

In certain embodiments, Compound 1 is a solid. In certain embodiments,Compound 1 is a hydrate. In certain embodiments, Compound 1 is solvated.In certain embodiments, Compound 1 is anhydrous.

In certain embodiments, Compound 1 is amorphous. In certain embodiments,Compound 1 is crystalline. In certain embodiments, Compound 1 is in acrystalline form described in U.S. Publication No. 2017/0283418, whichis incorporated herein by reference in its entirety. The solid forms ofCompound 1 can be prepared according to the methods described in thedisclosure of U.S. Publication No. 2017/0283418. The solid forms can bealso prepared according to other methods apparent to those of skill inthe art.

In one aspect, provided herein are stable formulations of Compound 1. Inone embodiment, the formulations of Compound 1 comprise a solid form ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide.In one embodiment, the formulations of Compound 1 comprise an amorphousform ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide.In one embodiment, the formulations of Compound 1 comprise a crystallineform ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide.

Formulations provided herein may be used in the preparation ofindividual, single unit dosage forms. Formulations and dosage formsprovided herein comprise Compound 1. Formulations and dosage forms canfurther comprise one or more excipients.

The formulations provided herein for oral administration can be providedas compressed capsules, tablets, tablet triturates, chewable lozenges,rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets, but arenot limited thereto.

5.2.1 Citrate Salt Form Y

Also provided herein are solid forms of Compound 1 that include citratesalts.

In certain embodiments, provided herein is citrate salt Form Y.

In one embodiment, the citrate salt Form Y is a solid form ofCompound 1. In another embodiment, the citrate salt Form Y iscrystalline. In another embodiment, the citrate salt Form Y is ananhydrate.

In certain embodiments, a solid form provided herein, e.g., Form Y is acitrate salt of Compound 1, and is substantially crystalline, asindicated by, e.g., X-ray powder diffraction measurements. In oneembodiment, a solid form provided herein, e.g., Form Y, has one or morecharacteristic X-ray powder diffraction peaks at approximately 4.8, 6.6,9.6, 13.6, 14.4, 15.4, 16.0, 16.9, 18.0, 18.9, 19.2, 19.9, 20.1, 20.9,21.8, 22.4, 22.7, 23.2, 23.4, 24.0, 24.1, 24.3, 25.1, 26.7, 27.0, 27.9,28.5, 29.0, 29.6, 30.2, 30.4, 30.8, 31.1, 31.6, 32.3, 33.1, 33.5, 34.0,34.6, or 35.1° 2θ (0.2° 2θ) or (0.1° 2θ). In a specific embodiment, asolid form provided herein, e.g., Form Y, has one, two, three, four,five, six, seven, eight, nine, ten, or eleven characteristic X-raypowder diffraction peaks at approximately 4.8, 6.6, 9.6, 15.4, 16.0,16.9, 18.9, 19.2, 19.9, 20.9, or 28.5° 2θ (0.2° 2θ). In anotherembodiment, a solid form provided herein has one, two, three, or fourcharacteristic X-ray powder diffraction peaks at approximately 4.8, 9.6,18.9, or 19.2° 2θ (0.2° 2θ). In one embodiment, the solid form iscitrate salt Form Y. In another embodiment, the citrate salt Form Y hasone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four,twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine,thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five,thirty-six, thirty-seven, thirty-eight, thirty-nine, or fortycharacteristic X-ray powder diffraction peaks.

In certain embodiments, the crystalline form exhibits a TGA thermogramcomprising a total mass loss of approximately 0.1% of the total mass ofthe sample between approximately 50° C. and approximately 150° C. whenheated from approximately 50° C. to approximately 220° C.

In one embodiment, provided herein is a crystalline citrate salt ofCompound 1 having a DSC thermogram comprising an endothermic event withan onset temperature of about 213° C. and a peak maximum temperature atabout 217° C. when heated from approximately 25° C. to approximately260° C.

In still another embodiment, the citrate salt Form Y is substantiallypure. In certain embodiments, the substantially pure citrate salt Form Yis substantially free of other solid forms, e.g., amorphous solid. Incertain embodiments, the purity of the substantially pure citrate saltForm Y is no less than about 95%, no less than about 96%, no less thanabout 97%, no less than about 98%, no less than about 98.5%, no lessthan about 99%, no less than about 99.5%, or no less than about 99.8%.

5.2.2 Citrate Salt Form Z

In certain embodiments, provided herein is a citrate salt Form Z.

In one embodiment, the citrate salt Form Z is a solid form ofCompound 1. In another embodiment, the citrate salt Form Z iscrystalline. In another embodiment, the citrate salt Form Z is ananhydrate. In another embodiment, the citrate salt Form Z is a hydrate.In one embodiment, the citrate salt Form Z is a non-stoichiometrichydrate. In still another embodiment, the citrate salt Form Z is achannel hydrate. In still another embodiment, the citrate salt Form Z isa non-stoichiometric channel hydrate. In still another embodiment, thecitrate salt Form Z is a solvate.

In certain embodiments, a solid form provided herein, e.g., Form Z, issubstantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, a solid form providedherein, e.g., Form Z, has one or more characteristic X-ray powderdiffraction peaks at approximately 4.6, 6.6, 9.4, 13.1, 14.1, 15.3,15.6, 17.4, 18.8, 19.0, 19.9, 20.4, 21.1, 21.9, 22.2, 22.7, 23.5, 23.9,25.2, 26.3, 26.8, 27.8, 28.3, 28.7, 29.8, 31.2, 31.9, 32.6, 33.7, 35.1,35.9, 37.4, or 38.0° 2θ (0.2° 2θ) or (0.1° 2θ). In a specificembodiment, a solid form provided herein has one, two, three, or fourcharacteristic X-ray powder diffraction peaks at approximately 9.4,18.8, 19.0, or 28.7° 2θ (0.2° 2θ). In one embodiment, the solid form iscitrate salt Form Z. In another embodiment, the citrate salt Form Z hasone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four,twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine,thirty, thirty-one, thirty-two, or thirty-three characteristic X-raypowder diffraction peaks.

In certain embodiments, the crystalline form exhibits a TGA thermogramcomprising a total mass loss of approximately 0.1% of the total mass ofthe sample between approximately 50° C. and approximately 150° C. whenheated from approximately 25° C. to approximately 300° C. In certainembodiments, the crystalline form is an anhydrate of Compound 1.

In one embodiment, provided herein is a crystalline citrate salt Form ofCompound 1 having a DSC thermogram comprising an endothermic event withan onset temperature at about 217° C. and a peak maximum temperature atabout 221° C. when heated from approximately 25° C. to approximately260° C.

In certain embodiments, the hydrate exhibits a TGA thermogram comprisinga total mass loss of approximately 2% of the total mass of the samplebetween approximately 25° C. and approximately 200° C. when heated fromapproximately 25° C. to approximately 300° C. In certain embodiments,the crystalline form is a hydrate of the Citrate form of Compound 1.

In certain embodiments, the non-stoichiometric hydrate form exhibits aTGA thermogram comprising a total mass loss of approximately 1.7% of thetotal mass of the sample between approximately 50° C. and approximately200° C. when heated from approximately 50° C. to approximately 300° C.In certain embodiments, the crystalline form is a non-stoichiometrichydrate of the Citrate form of Compound 1.

In certain embodiments, the solvate exhibits a TGA thermogram comprisinga total mass loss of approximately 1.3% of the total mass of the samplebetween approximately 25° C. and approximately 200° C. when heated fromapproximately 25° C. to approximately 300° C. In certain embodiments,the crystalline form is a solvate of the Citrate form of Compound 1.

In still another embodiment, the citrate salt Form Z is substantiallypure. In certain embodiments, the substantially pure citrate salt Form Zis substantially free of other solid forms, e.g., amorphous solid. Incertain embodiments, the purity of the substantially pure citrate saltForm Z is no less than about 95%, no less than about 96%, no less thanabout 97%, no less than about 98%, no less than about 98.5%, no lessthan about 99%, no less than about 99.5%, or no less than about 99.8%.

Form Y and Form Z of the citrate salt of Compound 1 can be preparedaccording to the methods described in the Examples provided herein or asdescribed in U.S. Publication No. 2017/0283418 A1, the disclosure ofwhich is incorporated herein by reference in its entirety. The solidforms can be also synthesized according to other methods apparent tothose of skill in the art based upon the teaching herein.

5.2.3 Capsules

Provided herein are capsules comprising Compound 1. In certainembodiments, the capsule comprises a citrate salt of Compound 1. Inanother embodiment, the capsule comprises a citrate salt of Compound 1and sodium lauryl sulfate.

In one embodiment, a capsule comprises Compound 1. In one embodiment,the capsule comprises an excipient. In one embodiment, the capsulecomprises tocophersolan (“TPGS”). In certain embodiments, the capsulecomprises 20-30%, 30%-40%,40%-50%, or 50%-60% Compound 1 by weight. Incertain embodiments, the capsule comprises 35-45%, 45%-55%, or 55%-65%excipient by weight. In certain embodiments, the capsule comprises 5-15%TPSG by weight. In certain embodiments, the capsule comprises 20-30%Compound 1 by weight, 60-70% excipient by weight, and 5-15% TPGS byweight. In certain embodiments, the capsule comprises 45-55% Compound 1by weight, 35-45% excipient by weight, and 5-15% TPGS by weight. Incertain embodiments, the capsule comprises 45-55% of Compound 1 byweight and 45-55% of excipient by weight. In certain embodiments, theexcipient is hydroxypropyl methylcellulose (“HPMC”). In certainembodiments, the excipient is polyvinlylacetate phthalate polymer(“PVA-P”). In certain embodiments, the excipient isvinylpyrrolidone-vinyl acetate copolymer (“PVP VA64”).

In certain embodiments, provided herein is a capsule formulationcomprising 35-45% Compound 1 by weight, 50-60% HPMC by weight, and 5-15%TPGS by weight. In certain embodiments, the capsule comprises 37%Compound 1 by weight, 53% HPMC by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 20-30% Compound 1 by weight, 60-70% HPMC by weight, and 5-15%TPGS by weight. In certain embodiments, the capsule comprises 25%Compound 1 by weight, 65% HPMC by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 20-30% Compound 1 by weight, 60-70% PVA-P by weight, and5-15% TPGS by weight. In certain embodiments, the capsule comprises 25%Compound 1 by weight, 65% PVA-P by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 20-30% Compound 1 by weight, 60-70% PVP V64 by weight, and5-15% TPGS by weight. In certain embodiments, the capsule comprises 25%Compound 1 by weight, 65% PVP VA64 by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 45-55% Compound 1 by weight, 35-45% HPMC by weight, and 5-15%TPGS by weight. In certain embodiments, the capsule comprises 50%Compound 1 by weight, 40% HPMC by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 45-55% Compound 1 by weight, 35-45% PVA-P by weight, and5-15% TPGS by weight. In certain embodiments, the capsule comprises 50%Compound 1 by weight, 40% PVA-P by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 45-55% Compound 1 by weight, 35-45% PVP VA64 by weight, and5-15% TPGS by weight. In certain embodiments, the capsule comprises 50%Compound 1 by weight, 40% PVP VA64 by weight, and 10% TPGS by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 45-55% Compound 1 by weight and 45-55% HPMC by weight. Incertain embodiments, the capsule comprises 50% Compound 1 by weight and50% HPMC by weight.

In certain embodiments, provided herein is a capsule formulationcomprising 45-55% Compound 1 by weight and 45-55% PVA-P by weight. Incertain embodiments, the capsule comprises 50% Compound 1 by weight and50% PVA-P by weight.

In certain embodiments, provided herein is a capsule formulationcomprising an amount of Compound 1 in gelatin capsules. In certainembodiments, the amount of Compound 1 is 100-150 mg. In certainembodiments, the amount of Compound 1 is 125 mg.

In certain embodiments, provided herein is a capsule formulationcomprising an amount of Compound 1 in HPMC capsules. In certainembodiments, the amount of Compound 1 is 100-150 mg. In certainembodiments, the amount of Compound 1 is 125 mg.

In certain embodiments, provided herein is a capsule formulationcomprising Compound 1 and microcrystalline cellulose (Avicel) in agelatin capsule. In certain embodiments, the capsule further comprisessodium laureth sulfate. In certain embodiments, Compound 1 and Avicelare present in the capsule in a 2:1 ratio. In certain embodiments, thetotal weight of Compound 1 and Avicel is between 100-120 mg. In certainembodiments, the total weight of Compound 1 and Avicel is 110 mg.

In certain embodiments, the capsule comprises a citrate salt of Compound1, microcrystalline cellulose (e.g., Avicel PH102), mannitol (e.g.,Parteck M200), citric acid; sodium lauryl sulfate, crosslinkedpolyvinylpyrrolidone (e.g., Kollidon CL), colloidal silicon dioxide, andstearic acid. In certain embodiments, the capsule comprises 5-25% of acitrate salt of Compound 1 by weight, 15-60% microcrystalline cellulose(e.g., Avicel PH102) by weight, 15-60% mannitol (e.g., Parteck M200) byweight, 5-20% citric acid by weight; 2.5-10% sodium lauryl sulfate byweight, 2-8% crosslinked polyvinylpyrrolidone (e.g., Kollidon CL) byweight, 0.3-1.5% colloidal silicon dioxide by weight, and 0.5-2% stearicacid by weight. In certain embodiments, the capsule comprises about13.36% of a citrate salt of Compound 1 by weight, about 33.02%microcrystalline cellulose (e.g., Avicel PH102) by weight, about 33.02%mannitol (e.g., Parteck M200) by weight, about 10% citric acid byweight; about 5% sodium lauryl sulfate by weight, about 4% crosslinkedpolyvinylpyrrolidone (e.g., Kollidon CL) by weight, about 0.6% colloidalsilicon dioxide by weight, and about 1% stearic acid by weight. Incertain embodiments, the capsule comprises 5-25% of a citrate salt ofCompound 1 by weight and 2.5-10% sodium lauryl sulfate by weight. Incertain embodiments, the capsule comprises about 13.36% of a citratesalt of Compound 1 by weight and about 5% sodium lauryl sulfate byweight.

In certain embodiments, the capsule comprises a citrate salt of Compound1 and sodium lauryl sulfate. In certain embodiments, the capsulecomprises 0.5-3% of a citrate salt of Compound 1 by weight and 0.5-3%sodium lauryl sulfate by weight. In certain embodiments, the capsulecomprises about 1.79% of a citrate salt of Compound 1 by weight andabout 1.0% sodium lauryl sulfate by weight. In certain embodiments, thecapsule comprises 2-12% of a citrate salt of Compound 1 by weight and0.5-3% sodium lauryl sulfate by weight. In certain embodiments, thecapsule comprises about 6.70% of a citrate salt of Compound 1 by weightand about 1.0% sodium lauryl sulfate by weight. In certain embodiments,the capsule comprises 5-20% of a citrate salt of Compound 1 by weightand 0.5-3% sodium lauryl sulfate by weight. In certain embodiments, thecapsule comprises about 10.72% of a citrate salt of Compound 1 by weightand about 1.0% sodium lauryl sulfate by weight.

In certain embodiments, the capsule comprises a citrate salt of Compound1, microcrystalline cellulose (e.g., Avicel PH102), Mannitol (e.g.,Parteck M200), sodium lauryl sulfate, fumaric acid, crospovidone, fumedsilica (e.g., Aerosil 200), and magnesium stearate. In certainembodiments, the capsule comprises 0.5-3% of a citrate salt of Compound1 by weight, 10-30% microcrystalline cellulose (e.g., Avicel PH102) byweight, 55-75% mannitol (e.g., Parteck M200) by weight, 0.5-3% sodiumlauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidoneby weight, 0.2-1% aerosol 200 by weight, and 0.5-3% magnesium stearateby weight. In certain embodiments, the capsule comprises about 1.79% ofa citrate salt of Compound 1 by weight, about 21.65% microcrystallinecellulose (e.g., Avicel PH102) by weight, about 64.96% mannitol (e.g.,Parteck M200) by weight, about 1.0% sodium lauryl sulfate by weight,about 5.0% fumaric acid by weight, about 4.0% crospovidone by weight,about 0.6% fumed silica (e.g., Aerosil 200) by weight, and about 1.0%magnesium stearate by weight. In certain embodiments, the capsulecomprises 0.5-3% of a citrate salt of Compound 1 by weight and 0.5-3%sodium lauryl sulfate by weight. In certain embodiments, the capsulecomprises about 1.79% of a citrate salt of Compound 1 by weight andabout 1.0% sodium lauryl sulfate by weight.

In certain embodiments, the capsule comprises 2-12% of a citrate salt ofCompound 1 by weight, 10-30% microcrystalline cellulose (e.g., AvicelPH102) by weight, 50-70% mannitol (e.g., Parteck M200) by weight, 0.5-3%sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7%crospovidone by weight, 0.2-1% fumed silica (e.g., Aerosil 200) byweight, and 0.5-3% magnesium stearate by weight. In certain embodiments,the capsule comprises about 6.70% of a citrate salt of Compound 1 byweight, about 20.42% microcrystalline cellulose (e.g., Avicel PH102) byweight, about 61.28% mannitol (e.g., Parteck M200) by weight, about 1.0%sodium lauryl sulfate by weight, about 5.0% fumaric acid by weight,about 4.0% crospovidone by weight, about 0.6% fumed silica (e.g.,Aerosil 200) by weight, and about 1.0% magnesium stearate by weight. Incertain embodiments, the capsule comprises 2-12% of a citrate salt ofCompound 1 by weight and 0.5-3% sodium lauryl sulfate by weight. Incertain embodiments, the capsule comprises about 6.70% of a citrate saltof Compound 1 by weight and about 1.0% sodium lauryl sulfate by weight.

In certain embodiments, the capsule comprises 5-20% of a citrate salt ofCompound 1 by weight, 10-30% microcrystalline cellulose (e.g., AvicelPH102) by weight, 50-70% mannitol (e.g., Parteck M200) by weight, 0.5-3%sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7%crospovidone by weight, 0.2-1% fumed silica (e.g., Aerosil 200) byweight, and 0.5-3% magnesium stearate by weight. In certain embodiments,the capsule comprises about 10.72% of a citrate salt of Compound 1 byweight, about 19.41% microcrystalline cellulose (e.g., Avicel PH102) byweight, about 58.27% mannitol (e.g., Parteck M200) by weight, about 1.0%sodium lauryl sulfate by weight, about 5.0% fumaric acid by weight,about 4.0% crospovidone by weight, about 0.6% fumed silica (e.g.,Aerosil 200) by weight, and about 1.0% magnesium stearate by weight. Incertain embodiments, the capsule comprises 5-20% of a citrate salt ofCompound 1 by weight and 0.5-3% sodium lauryl sulfate by weight. Incertain embodiments, the capsule comprises about 10.72% of a citratesalt of Compound 1 by weight and about 1.0% sodium lauryl sulfate byweight. 5.2.4 Tablets

Provided herein are tablets comprising Compound 1. In certainembodiments, Compound 1 is an HCl salt. In certain embodiments, Compound1 is a citrate salt.

In certain embodiments, provided herein is a tablet comprising Compound1 and a filler, disintegrant, lubricant, acidifier, surfactant, polymer,and/or glidant. In certain embodiments, the filler is microcrystallinecellulose (e.g., Avicel PH102), mannitol, lactose, or starch. In certainembodiments, the disintegrant is croscarmellose sodium (e.g.,Ac-Di-sol), sodium starch glycolate, or Kollidon CL. In certainembodiments, the lubricant is magnesium stearate, stearic acid, orsodium stearyl fumarate. In certain embodiments, the acidifier istartaric acid, fumaric acid, or citric acid. In certain embodiments, thesurfactant is sodium lauryth sulfate, VE-TPGS, or hydrogenated CastorOil. In certain embodiments, the polymer is HEC, HPC, PEG4000, PVP K30,Pluronic F127, PVP VA64, or SB-beta-CD. In certain embodiments, theglidant is aerosol 200. In certain embodiments, the ratio of Compound 1to filler is about 1:5. In certain embodiment, the ratio of Compound 1to disintegrant is about 2:1. In certain embodiments, the ratio ofCompound 1 to lubricant is about 20:1. In certain embodiments, the ratioof Compound 1 to acidifier is about 1:1. In certain embodiments, theratio of Compound 1 to surfactant is about 20:1. In certain embodiments,the ratio of Compound 1 to polymer is about 1:2. In certain embodiments,the ratio of Compound 1 to glidant is about 20:1.

In certain embodiments, provided herein is a tablet comprising 15-25% ofCompound 1 by weight, 32-43% of microcrystalline cellulose (e.g., AvicelPH102) by weight, 32-43% of mannitol (e.g., Emprove Parteck) by weight,2-6% of croscarmellose sodium (e.g., Ac-Di-Sol) by weight, 0.3-0.7% offumed silica (e.g., Aerosil 200) by weight, and 0.5-1.5% magnesiumstearate by weight. In certain embodiments, the tablet comprises 20% ofCompound 1 by weight, 37.25% of microcrystalline cellulose (e.g., AvicelPH102) by weight, 37.25% of mannitol (e.g., Emprove Parteck) by weight,4% of croscarmellose sodium (e.g., Ac-Di-Sol) by weight, 0.5% of fumedsilica (e.g., Aerosil 200) by weight, and 1% magnesium stearate byweight. In certain embodiments, the total weight of the tablet isbetween 225-275 mg. In certain embodiments, the total weight of thetablet is 250 mg. In certain embodiments, Compound 1 is an HCl salt. Incertain embodiments, Compound 1 is a citrate salt.

In certain embodiments, provided herein is a tablet comprising 15-25% ofCompound 1 by weight, 32-43% of microcrystalline cellulose (e.g., AvicelPH102) by weight, 32-43% of mannitol (e.g., Emprove Parteck) by weight,2-6% of croscarmellose sodium (e.g., Ac-Di-Sol) by weight, 0.3-0.7% offumed silica (e.g., Aerosil 200) by weight, and 0.5-1.5% magnesiumstearate by weight. In certain embodiments, the tablet comprises 20% ofCompound 1, 37.25% of microcrystalline cellulose (e.g., Avicel PH102) byweight, 37.25% of mannitol (e.g., Emprove Parteck) by weight, 4% ofcroscarmellose sodium (e.g., Ac-Di-Sol) by weight, 0.5% of fumed silica(e.g., Aerosil 200) by weight, and 1% magnesium stearate by weight. Incertain embodiments, the total weight of the tablet is between 225-275mg. In certain embodiments, the total weight of the tablet is 250 mg.

In certain embodiments, provided herein is a tablet comprising 15-25% ofan HCl salt of Compound 1 by weight, 32-43% of microcrystallinecellulose (e.g., Avicel PH102) by weight, 32-43% of mannitol (e.g.,Emprove Parteck) by weight, 2-6% of croscarmellose sodium (e.g.,Ac-Di-Sol) by weight, 0.3-0.7% of fumed silica (e.g., Aerosil 200) byweight, and 0.5-1.5% magnesium stearate by weight. In certainembodiments, the tablet comprises 20% of a HCl salt of Compound 1 byweight, 37.25% of microcrystalline cellulose (e.g., Avicel PH102) byweight, 37.25% of mannitol (e.g., Emprove Parteck) by weight, 4% ofcroscarmellose sodium (e.g., Ac-Di-Sol) by weight, 0.5% of fumed silica(e.g., Aerosil 200) by weight, and 1% magnesium stearate by weight. Incertain embodiments, the total weight of the tablet is between 225-275mg. In certain embodiments, the total weight of the tablet is 250 mg.

In certain embodiments, provided herein is a tablet comprising 15-25% ofa citrate salt of Compound 1 by weight, 32-43% of microcrystallinecellulose (e.g., Avicel PH102) by weight, 32-43% of mannitol (e.g.,Emprove Parteck) by weight, 2-6% of croscarmellose sodium (e.g.,Ac-Di-Sol) by weight, 0.3-0.7% of fumed silica (e.g., Aerosil 200) byweight, and 0.5-1.5% magnesium stearate by weight. In certainembodiments, the tablet comprises 20% of a citrate salt of Compound 1 byweight, 37.25% of microcrystalline cellulose (e.g., Avicel PH102) byweight, 37.25% of mannitol (e.g., Emprove Parteck) by weight, 4% ofcroscarmellose sodium (e.g., Ac-Di-Sol) by weight, 0.5% of fumed silica(e.g., Aerosil 200) by weight, and 1% magnesium stearate by weight. Incertain embodiments, the total weight of the tablet is between 225-275mg. In certain embodiments, the total weight of the tablet is 250 mg.

5.2.5 Spray Dried Dispersion Formulation

In certain embodiments, provided herein is a spray dried dispersionformulation of Compound 1.

In certain embodiments, the spray dried dispersion formulation providedherein can be obtained by a spray-drying process of Compound 1substantially as shown in FIG. 60. In certain embodiments, thespray-drying process comprises 1) mixing Compound 1 and an excipientwith a solvent (e.g., acetone, methanol, water or a mixture thereof); 2)heating the mixture to a certain temperature (e.g., about 80° C.); 3)spray-drying the mixture; and 4) collecting resulting solids. In certainembodiments, the excipient is a polymer. In another embodiment, theexcipient is a polymer selected from a group consisting of HPMCAS-M, PVPVA64, PVA-P and HPMC E3. In one embodiment, the solvent is acetone. Inanother embodiment, the solvent is a mixture of methanol and water(e.g., v/v 9:1) or a mixture of acetone and water (e.g., v/v 9:1).

In certain embodiments, the spray dried dispersion formulation comprisesCompound 1 free base, HPMC, TPGS, microcrystalline cellulose (e.g.,Avicel PH102), mannitol, crosslinked polyvinylpyrrolidone (e.g.,Kollidon CL), colloidal silicon dioxide, and stearic acid. In certainembodiments, the spray dried dispersion formulation comprises about10-40% of Compound 1 free base by weight, about 15-60% HPMC by weight,about 2-10% TPGS by weight, about 10-40% microcrystalline cellulose(e.g., Avicel PH102) by weight, about 10-40% mannitol by weight, about2-8% crosslinked polyvinylpyrrolidone (e.g., Kollidon CL) by weight,about 0.3-1.5% colloidal silicon dioxide by weight, and about 0.5-2%stearic acid by weight. In certain embodiments, the spray drieddispersion formulation comprises about 20% of Compound 1 free base byweight, about 28.6% HPMC by weight, about 5.4% TPGS by weight, about20.2% microcrystalline cellulose (e.g., Avicel PH102) by weight, about20.2% mannitol by weight, about 4% crosslinked polyvinylpyrrolidone(e.g., Kollidon CL) by weight, about 0.6% colloidal silicon dioxide byweight, and about 1% stearic acid by weight.

5.3 Kits

Pharmaceutical packs or kits which comprise pharmaceutical compositionsor dosage forms provided herein are also provided. Exemplary kitsinclude notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

5.4 Methods of Use

The formulations of Compound 1 described herein have utility aspharmaceuticals to treat, prevent or improve conditions in animals orhumans. Accordingly, provided herein are formulations of Compound 1described herein that can be used in all the methods as provided herein.Particularly, the formulations of Compound 1 as provided herein are foruses in methods for the treatment or prevention of a cancer. Forexample, the formulations of Compound 1 as provided herein are for usesin methods for the treatment of a cancer. The methods provided hereincomprise the administration of an effective amount of one or moreformulations of Compound 1 described herein to a subject in needthereof. It is to be understood that the methods described herein alsoinclude treatment with a pharmaceutical composition, such as thoseprovided below.

In another aspect, provided herein are methods for treating orpreventing a cancer, comprising administering to a subject in needthereof an effective amount of a formulation of Compound 1, as describedherein. In some embodiments, the cancer is a solid tumor or ahematological tumor. In some embodiments, the cancer is not melanoma.

In some embodiments, the solid tumor is melanoma, colorectal cancer,stomach cancer, head and neck cancer, thyroid cancer, bladder cancer,CNS cancer, lung cancer, pancreatic cancer, and soft tissue cancer. Inone embodiment, the solid tumor is endocrine cancer, bladder cancer,breast cancer, cervix cancer, colon cancer, duodenum cancer, glioma,head and d neck cancer, kidney cancer, liver cancer, lung cancer (e.g.non-small cell lung cancer NSCLC), esophageal cancer, thyroid cancer, orpancreatic cancer.

In other embodiments, the cancer is bladder cancer, breast cancer (forexample Her positive, Her negative, or EGFR positive breast cancer), CNScancer (including neuroblastoma, and glioma), colon cancer,gastrointestinal cancer (for example, stomach cancer, and colon cancer),endocrine cancer (for example, thyroid cancer, or adrenal gland cancer),female genitoureal cancer (for example, cervix cancer, ovary clear cellcancer, vulva cancer, uterus cancer, or ovary cancer), head and neckcancer, hematopoietic cancer (for example, leukemia or myeloma), kidneycancer, liver cancer, lung cancer (for example, NSCLC, or SCLC),melanoma, pancreas cancer, prostate cancer, or soft tissue cancer (forexample, sarcoma, or osteosarcoma).

Also provided herein are methods for treating or preventinghepatocellular carcinoma (HCC), comprising administering to a subject inneed thereof an effective amount of a formulation of Compound 1, asdescribed herein.

Also provided herein are methods for treating or preventing colorectalcancer (CRC), melanoma, gastric cancer, HCC, lung cancer, pancreaticcancer, leukemia, or multiple myeloma, comprising administering to asubject in need thereof an effective amount of a formulation of Compound1 as described herein or a pharmaceutical composition thereof, asdescribed herein. In one embodiment, the CRC, gastric cancer, or HCC isa cancer characterized by a P-catenin mutation. Also provided herein aremethods for treating or preventing colorectal cancer (CRC), gastriccancer, HCC, lung cancer, pancreatic cancer, leukemia, and multiplemyeloma, comprising administering to a subject in need thereof aneffective amount of a formulation of Compound 1 as described herein, asdescribed herein.

In another embodiment provided herein are methods of treating leukemiacomprising administering a formulation of Compound 1 as described hereinor a pharmaceutical composition thereof. The leukemia can be chronicmyelogenous leukemia (CML). In another embodiment, the leukemia is acutemyelogenous leukemia (AML). In one embodiment, the leukemia is FLT-3mutated AML.

In another embodiment provided herein are methods of treating lymphomacomprising administering a formulation of Compound 1 as described hereinor a pharmaceutical composition thereof. The lymphoma can be Burkitt'slymphoma. In one embodiment, the leukemia is Hodgkin's lymphoma. Inanother embodiment, the leukemia is a B-cell lymphoma. In anotherembodiment, the leukemia is a T-cell lymphoma. In still anotherembodiment, the lymphoma is primary effusion lymphoma (PEL).

The formulations of Compound 1 show anti-proliferative activity in avariety of cancer cell lines. Anti-proliferative activity in thesecancer cell lines indicates that the formulations of Compound 1 areuseful in the treatment of cancers, including hematopoietic and solidtumors. In one embodiment, the hematopoietic and solid tumors areselected from bladder cancer, breast cancer, CNS cancer (for example,neuroblastoma, medulloblastoma and glioma), colon cancer, duodenumcancer, endocrine cancer (for example, thyroid cancer and adrenal glandcancer), female genitourinary cancer (for example, uterus cancer, cervixcancer, ovary cancer and vulva cancer), head and neck cancer (forexample, esophageal cancer), hematopoietic and lymphoid cancer (forexample, lymphoma, leukemia, and myeloma), kidney cancer, liver cancer,lung cancer (for example, NSCLC and SCLC), pancreas cancer, prostatecancer, skin cancer (for example, melanoma and carcinoma), soft tissuecancer (for example, sarcoma and osteosarcoma), stomach cancer, andtestis cancer. In one embodiment, the hematopoietic and solid tumors areselected from bladder cancer, breast cancer, CNS cancer (for example,neuroblastoma, medulloblastoma and glioma), colon cancer, duodenumcancer, endocrine cancer (for example, thyroid cancer and adrenal glandcancer), female genitourinary cancer (for example, uterus cancer, cervixcancer, and vulva cancer), head and neck cancer, hematopoietic andlymphoid cancer (for example, lymphoma, leukemia, and myeloma), kidneycancer, liver cancer, lung cancer (for example, NSCLC and SCLC),pancreas cancer, prostate cancer, skin cancer (for example, melanoma andcarcinoma), soft tissue cancer (for example, sarcoma and osteosarcoma),stomach cancer, and testis cancer.

In another embodiment, the formulations of Compound 1 described hereininduce apoptosis in a variety of cancer cell lines. Induction ofapoptosis indicates that the formulations of Compound 1 described hereinare useful in the treatment of cancers, including hematopoietic andsolid tumors. In one embodiment, the hematopoietic and solid tumors areselected from bladder cancer, breast cancer, CNS cancer (for example,neuroblastoma, and glioma), colon cancer, duodenum cancer, endocrinecancer (for example, thyroid cancer and adrenal gland cancer), femalegenitourinary cancer (for example, uterus cancer, cervix cancer, ovarycancer and vulva cancer), head and neck cancer (for example, esophagealcancer), hematopoietic and lymphoid cancer (for example, lymphoma,leukemia, and myeloma), kidney cancer, liver cancer, lung cancer (forexample, NSCLC and SCLC), pancreas cancer, prostate cancer, skin cancer(for example, melanoma and carcinoma), soft tissue cancer (for example,sarcoma and osteosarcoma), stomach cancer, and testis cancer. In oneembodiment, the hematopoietic and solid tumors are selected from bladdercancer, breast cancer, CNS cancer (for example, neuroblastoma, andglioma), colon cancer, duodenum cancer, endocrine cancer (for example,thyroid cancer and adrenal gland cancer), female genitourinary cancer(for example, vulva cancer), head and neck cancer (for example,esophageal cancer), hematopoietic and lymphoid cancer (for example,lymphoma, and leukemia), kidney cancer, liver cancer, lung cancer (forexample, NSCLC and SCLC), pancreas cancer, prostate cancer, skin cancer(for example, melanoma), soft tissue cancer (for example, sarcoma andosteosarcoma), stomach cancer, and testis cancer. In one embodiment, thehematopoietic and solid tumors are selected from bladder cancer, breastcancer, CNS cancer (for example, medulloblastoma, neuroblastoma, andglioma), colon cancer, duodenum cancer, endocrine cancer (for example,thyroid cancer and adrenal gland cancer), female genitourinary cancer(for example, placenta cancer, uterus cancer, cervix cancer, ovarycancer and vulva cancer), head and neck cancer (for example, esophagealcancer), hematopoietic and lymphoid cancer (for example, lymphoma,leukemia, and myeloma), kidney cancer, liver cancer, lung cancer (forexample, NSCLC and SCLC), pancreas cancer, prostate cancer, skin cancer(for example, melanoma and carcinoma), soft tissue cancer (for example,sarcoma and osteosarcoma), stomach cancer, and testis cancer.

Also provided herein are methods for treating or preventing a cancercharacterized by a BRAF mutation and/or a beta-catenin mutation(alternatively referred to as CTNNB1 mutation), comprising administeringto a subject in need thereof an effective amount of a formulation ofCompound 1, as described herein. In some such embodiments, the cancer ischaracterized by a BRAF mutation. In another embodiment, the cancer ischaracterized by a beta-catenin mutation. In yet another embodiment, thecancer is characterized by an activated beta-catenin pathway. In somesuch embodiments, the cancer is CRC or melanoma characterized by a BRAFmutation. In other embodiments, the cancer is CRC characterized by abeta-catenin mutation, additionally comprising an EGFR mutation orincreased EGFR activity (for example, CRC characterized by an activatedbeta-catenin pathway and an EGFR mutation, or CRC characterized by anactivated beta-catenin pathway and increased EGFR activity). In stillother embodiments, the cancer is gastric cancer characterized by abeta-catenin mutation, additionally comprising a KRAS mutation (i.e.gastric cancer characterized by an activated beta-catenin pathway and aKRAS mutation). In another embodiment the cancer is HCC, characterizedby an activated beta-catenin pathway. In some such embodiments, the BRAFmutation is BRAF V660E. In some such embodiments, the BRAF mutation isBRAF V600E. In some such embodiments, the BRAF mutation is one or moreof BRAF V600E, BRAF T119S, or BRAF G596R. In some such embodiments, thebeta-catenin mutation is one or more of beta-catenin S33Y, G34E, S45del,or S33C. In some such embodiments, the EGFR mutation is one or more ofEGFR E282K, G719S, P753S, or V1011M. In some such embodiments, the KRASmutation is A146T, G12C, G12D, G12V, G3D, or Q61L.

Also provided herein are methods for treating or preventing a cancerexpressing PD-L1, comprising administering to a subject in need thereofan effective amount of a formulation of Compound 1, as described herein.In some such embodiments, the PD-L1 expressing cancer is melanoma, lungcancer, renal cell carcinoma (RCC), or HCC.

Also provided herein are methods for treating or preventing a cancercharacterized by a BRAF mutation, comprising administering to a subjectin need thereof an effective amount of a formulation of Compound 1, asdescribed herein. In some such embodiments, the cancer characterized bya BRAF mutation is CRC, thyroid cancer, melanoma or lung cancer. In somesuch embodiments, the cancer characterized by a BRAF mutation is CRC,thyroid cancer, or lung cancer. In some such embodiments, the BRAFmutation is BRAF V660E. In some such embodiments, the BRAF mutation isBRAF V600E. In other embodiments, the BRAF mutation is one or more ofBRAF V600E, BRAF T119S, or BRAF G596R.

Also provided herein are methods for treating or preventing a cancercharacterized by an NRAS mutation, comprising administering to a subjectin need thereof an effective amount of a formulation of Compound 1, asdescribed herein. In some such embodiments, the cancer characterized byan NRAS mutation is melanoma.

Also provided herein are methods for treating or preventing a cancercharacterized by a KRAS mutation, comprising administering to a subjectin need thereof an effective amount of a formulation of Compound 1, asdescribed herein. In some such embodiments, the cancer characterized bya KRAS mutation is CRC, pancreas cancer or lung cancer.

Also provided herein are methods for treating or preventing a cancercharacterized by a beta-catenin mutation, comprising administering to asubject in need thereof an effective amount of a formulation of Compound1, as described herein. Also provided herein are methods for treating orpreventing a cancer characterized by an activated beta-catenin pathway,comprising administering to a subject in need thereof an effectiveamount of a formulation of Compound 1, as described herein. In some suchembodiments, the cancer characterized by a beta-catenin mutation is CRC,stomach cancer, HCC or sarcoma. In some such embodiments, the cancercharacterized by an activated beta-catenin pathway is CRC, stomachcancer, HCC or sarcoma.

Also provided herein are methods for treating or preventinghepatocellular carcinoma (HCC), comprising administering to a subject inneed thereof an effective amount of a formulation of Compound 1, asdescribed herein. In some such embodiments, the HCC is characterized bya beta-catenin mutation and/or increased YAP expression. In some suchembodiments, the HCC is characterized by an activated beta-cateninpathway and/or increased YAP amplification expression. In someembodiments, the increased YAP expression is due to amplification or amutation.

Also provided herein are methods for treating or preventing colorectalcancer (CRC), comprising administering to a subject in need thereof aneffective amount of a formulation of Compound 1, as described herein. Insome such embodiments, the CRC is characterized by a BRAF mutationand/or beta-catenin mutation. In some such embodiments, the CRC ischaracterized by a BRAF mutation and/or an activated beta-cateninpathway.

Also provided herein are methods for treating or preventing gastriccancer, comprising administering to a subject in need thereof aneffective amount of a formulation of Compound 1, as described herein. Insome such embodiments, the gastric cancer is characterized by abeta-catenin mutation. In some such embodiments, the gastric cancer ischaracterized by an activated beta-catenin pathway.

Also provided herein are methods for treating or preventing melanoma,comprising administering to a subject in need thereof an effectiveamount of a formulation of Compound 1, as described herein. In some suchembodiments, the melanoma is characterized by a BRAF mutation and/orNRAS mutation.

Further provided herein are methods for predicting response to treatmentwith a formulation of Compound 1 described herein in a patient having acancer characterized by a gene mutation, the method comprising: a)obtaining a biological test sample from the patient's cancer; b)obtaining the gene sequence of one or more genes selected from BRAF,NRAS, KRAS, and/or CTNNB1 in said biological test sample; c) comparingsaid gene sequence(s) to the gene sequence(s) of a biological wild-typesample; wherein the presence of a mutation indicates an increasedlikelihood of response to a formulation of Compound 1 described hereintreatment of said patient's cancer. In some such embodiments, the methodadditionally comprises administering an effective amount of aformulation of Compound 1, as described herein.

Further provided herein are methods for predicting therapeutic efficacyof a formulation of Compound 1 described herein for treatment of apatient having a cancer characterized by a gene mutation, the methodcomprising: a) obtaining a biological test sample from the patient'scancer; b) obtaining the gene sequence(s) of one or more genes selectedfrom BRAF, NAS, KRAS, and/or CTNNB1 in said biological test sample; c)comparing said gene sequence(s) to the gene sequence(s) of a biologicalwild-type sample; wherein the presence of a mutation indicates anincreased likelihood of therapeutic efficacy of said treatment with aformulation of Compound 1 described herein for said patient. In somesuch embodiments, the method additionally comprises administering aneffective amount of a formulation of Compound 1, as described herein.

In some embodiments, provided herein are methods for treating andpreventing cancer metastasis, comprising administering to a subject inneed thereof an effective amount of a formulation of Compound 1, asdescribed herein. In some embodiments, the cancer is a metastaticcancer, in particular, a metastatic solid tumor or metastatichematologic cancer, wherein the solid tumor and hematologic cancer is asdescribed herein. In other embodiments, provided herein are methods oftreating and preventing cancer metastasis, comprising administering to asubject in need thereof an effective amount of a formulation of Compound1, as described herein. In yet another aspect, provided herein ismethods of eradicating cancer stem cells in a subject, comprisingadministering to a subject in need thereof an effective amount of aformulation of Compound 1, as described herein. In other embodiments,provided herein are methods of inducing differentiation in cancer stemcells in a subject, comprising administering to a subject in needthereof an effective amount of a formulation of Compound 1, as describedherein. In other embodiments, provided herein are methods of inducingcancer stem cell death in a subject, comprising administering to asubject in need thereof an effective amount of a formulation of Compound1, as described herein. In some such embodiments, the cancer is a solidtumor or a hematological cancer, as described herein.

In one embodiment, provided herein are methods for achieving a ResponseEvaluation Criteria in Solid Tumors (RECIST 1.1) of complete response,partial response or stable disease in a patient comprising administeringan effective amount of a formulation of Compound 1 described herein to apatient having a cancer, in particular a solid tumor as describedherein. In another embodiment, provided herein are methods to increaseProgression Free Survival rates, as determined by Kaplan-Meierestimates.

In one embodiment, provided herein are methods for preventing ordelaying a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ofprogressive disease in a patient, comprising administering an effectiveamount of a formulation of Compound 1 described herein to a patienthaving a solid tumor as described herein. In one embodiment theprevention or delaying of progressive disease is characterized orachieved by a change in overall size of the target lesions, of forexample, between −30% and +20% compared to pre-treatment. In anotherembodiment, the change in size of the target lesions is a reduction inoverall size of more than 30%, for example, more than 50% reduction intarget lesion size compared to pre-treatment. In another, the preventionis characterized or achieved by a reduction in size or a delay inprogression of non-target lesions compared to pre-treatment. In oneembodiment, the prevention is achieved or characterized by a reductionin the number of target lesions compared to pre-treatment. In another,the prevention is achieved or characterized by a reduction in the numberor quality of non-target lesions compared to pre-treatment. In oneembodiment, the prevention is achieved or characterized by the absenceor the disappearance of target lesions compared to pre-treatment. Inanother, the prevention is achieved or characterized by the absence orthe disappearance of non-target lesions compared to pre-treatment. Inanother embodiment, the prevention is achieved or characterized by theprevention of new lesions compared to pre-treatment. In yet anotherembodiment, the prevention is achieved or characterized by theprevention of clinical signs or symptoms of disease progression comparedto pre-treatment, such as cancer-related cachexia or increased pain.

In certain embodiments, provided herein are methods for decreasing thesize of target lesions in a patient compared to pre-treatment,comprising administering an effective amount of a formulation ofCompound 1 described herein to a patient having a cancer, in particulara solid tumor as described herein.

In certain embodiments, provided herein are methods for decreasing thesize of a non-target lesion in a patient compared to pre-treatment,comprising administering an effective amount of a formulation ofCompound 1 described herein to a patient having a cancer, in particulara solid tumor as described herein.

In certain embodiments, provided herein are methods for achieving areduction in the number of target lesions in a patient compared topre-treatment, comprising administering an effective amount of aformulation of Compound 1 described herein to a patient having a cancer,in particular a solid tumor as described herein.

In certain embodiments, provided herein are methods for achieving areduction in the number of non-target lesions in a patient compared topre-treatment, comprising administering an effective amount aformulation of Compound 1 described herein to a patient having a cancer,in particular a solid tumor as described herein.

In certain embodiments, provided herein are methods for achieving adisappearance of all target lesions in a patient, comprisingadministering an effective amount of a formulation of Compound 1described herein to a patient having a cancer, in particular a solidtumor as described herein.

In certain embodiments, provided herein are methods for achieving adisappearance of all non-target lesions in a patient, comprisingadministering an effective amount of a formulation of Compound 1described herein to a patient having a cancer, in particular a solidtumor as described herein.

In certain embodiments, provided herein are methods for treating acancer, in particular a solid tumor as described herein, the methodscomprising administering an effective amount of a formulation ofCompound 1 described herein to a patient having a cancer, in particulara solid tumor, wherein the treatment results in a complete response,partial response or stable disease, as determined by Response EvaluationCriteria in Solid Tumors (RECIST 1.1).

In certain embodiments, provided herein are methods for treating acancer, in particular a solid tumor as described herein, the methodscomprising administering an effective amount of a formulation ofCompound 1 described herein to a patient having a cancer, in particulara solid tumor as described herein, wherein the treatment results in areduction in target lesion size, a reduction in non-target lesion sizeand/or the absence of new target and/or non-target lesions, compared topre-treatment.

In certain embodiments, provided herein are methods for treating acancer, in particular a solid tumor as described herein, the methodscomprising administering an effective amount a formulation of Compound 1described herein to a patient having a cancer, in particular a solidtumor as described herein, wherein the treatment results in preventionor retarding of clinical progression, such as cancer-related cachexia orincreased pain.

In another embodiment, provided herein are methods for inducing atherapeutic response characterized with the International WorkshopCriteria (IWC) for NHL (see Cheson B D, Pfistner B, Juweid, M E, et. al.Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007:(25) 579-586) of a patient, comprising administering an effective amounta formulation of Compound 1 described herein to a patient having acancer, in particular hematological cancers such as lymphoma, asdescribed herein. In another embodiment, provided herein are methods forachieving complete remission, partial remission or stable disease, asdetermined by the International Workshop Criteria (IWC) for NHL in apatient, comprising administering an effective amount of a formulationof Compound 1 described herein to a patient having a cancer, inparticular hematological cancers such as lymphoma, as described herein.In another embodiment, provided herein are methods for achieving anincrease in overall survival, progression-free survival, event-freesurvival, time to progression, disease-free survival or lymphoma-freesurvival as determined by the International Workshop Criteria (IWC) forNHL in a patient, comprising administering an effective amount of aformulation of Compound 1 described herein to a patient having a cancer,in particular hematological cancers such as lymphoma, as describedherein.

In another embodiment, provided herein are methods for inducing atherapeutic response assessed with the International Uniform ResponseCriteria for Multiple Myeloma (IURC) (see Durie B G M, Harousseau J-L,Miguel J S, et al. International uniform response criteria for multiplemyeloma. Leukemia, 2006; (10) 10: 1-7) of a patient, comprisingadministering an effective amount of a formulation of Compound 1 to apatient having a cancer, in particular multiple myeloma. In anotherembodiment, provided herein are methods for achieving a stringentcomplete response, complete response, very good partial response, orpartial response, as determined by the International Uniform ResponseCriteria for Multiple Myeloma (IURC) in a patient, comprisingadministering an effective amount of a formulation of Compound 1described herein to a patient having a cancer, in particular multiplemyeloma. In another embodiment, provided herein are methods forachieving an increase in overall survival, progression-free survival,event-free survival, time to progression, or disease-free survival in apatient, comprising administering an effective amount of a formulationof Compound 1 described herein to a patient having a cancer, inparticular multiple myeloma.

In another embodiment, provided herein are methods for inducing atherapeutic response assessed with the Response Assessment forNeuro-Oncology (RANO) Working Group for GBM (see Wen P., Macdonald, DR., Reardon, D A., et al. Updated response assessment criteria forhigh-grade gliomas: Response assessment in neuro-oncology working group.J. Clin. Oncol. 2010; 28: 1963-1972) of a patient, comprisingadministering an effective amount of a formulation of Compound 1described herein to a patient having a cancer, in particularglioblastoma multiforme (GBM). In one embodiment, RANO will be used toestablish the proportion of subjects progression-free at 6 months fromDay 1 of treatment relative to efficacy evaluable subjects in the GBMtype.

In another embodiment, provided herein are methods for improving theEastern Cooperative Oncology Group Performance Status (ECOG) of apatient, comprising administering an effective amount a formulation ofCompound 1 described herein to a patient having a cancer, in particulara solid tumor or hematological cancer as described herein.

In another embodiment, provided herein are methods for inducing atherapeutic response assessed by Positron Emission Tomography (PET)outcome of a patient, comprising administering an effective amount of aformulation of Compound 1 described herein to a patient having a cancer,in particular a solid tumor or hematological cancer as described herein.In certain embodiments, provided herein are methods for treating acancer, in particular a solid tumor or hematological cancer as describedherein, the methods comprising administering an effective amount of aformulation of Compound 1 described herein to a patient having a cancer,in particular a solid tumor or hematological cancer as described herein,wherein the treatment results in a reduction in tumor metabolicactivity, for example, as measured by PET imaging.

Further provided herein are methods for treating patients who have beenpreviously treated for a cancer, in particular a solid tumor or ahematological cancer as described herein, as well as those who have notpreviously been treated. Such methods include administration of aformulation of Compound 1 described herein. Because patients with acancer have heterogeneous clinical manifestations and varying clinicaloutcomes, the treatment given to a patient may vary, depending onhis/her prognosis. The skilled clinician will be able to readilydetermine without undue experimentation specific secondary agents, typesof surgery, and types of non-drug based standard therapy that can beeffectively used to treat an individual patient with a cancer.

A formulation of Compound 1 as provided herein can be use in any of theabove described methods.

6. EXAMPLES

The following Examples are presented by way of illustration, notlimitation. Compounds are named using the automatic name generating toolprovided in ChemBiodraw Ultra (Cambridgesoft), which generatessystematic names for chemical structures, with support for theCahn-Ingold-Prelog rules for stereochemistry. One skilled in the art canmodify the procedures set forth in the illustrative examples to arriveat the desired products.

Abbreviations used:

BHT Butylated hydroxytoluene CA Citric acid CU Content uniformity FaSSGFFasted state simulated gastric fluid FaSSIF Fasted state simulatedintestinal fluid FeSSGF Fed state simulated gastric fluid FeSSIF Fedstate simulated intestinal fluid FIH First in human HP-β-CDhydroxypropyl-beta-cyclodextrin HPC Hydroxypropyl cellulose HPMCHydroxypropyl methylcellulose MCC Microcrystalline cellulose PEGPolyethylene glycol PVA-P Polyvinlylacetate phthalate polymer PVP VA64Vinylpyrrolidone-vinyl acetate copolymer SA Stearic acid SD Spray-dryingSLS Sodium lauryl sulfate SMB Sodium metabisulfite SDD Spray-dryingdispersion SSF Sodium stearyl fumarate TPGS Tocophersolan

6.1 Preparation of Spray Dried Dispersion Formulations

Spray dried dispersion formulations of Compound were obtained from aspray-drying process of Compound 1 as depicted in FIG. 60. Thespray-drying process comprised: (1) mixing Compound 1 with a solvent at25° C. to yield a suspension; (2) heating the suspension to about 80° C.(78-88° C.); (3) spray-drying under the conditions in Table 1 or Table 2to yield a spray dried dispersion formulation; and (4) collecting theresulting solids.

TABLE 1 Spray-drying conditions part A Formulation Active Polymer SprayLoading- Loading Solution Dry in Solids Batch Wet Entry BasisFormulation Polymer Solution Content Size Yield No. [wt %] DescriptionType [wt %] Solvent [wt %] [g] [%] 1 10 10% HPMCAS-M 3.6 Acetone 4 2 100A:HPMCAS-M 2 25 25% HPMCAS-M 3.6 Acetone 4 0.8 87 A:HPMCAS-M 3 25 25%PVP VA64 3.6 Acetone 4 0.8 82 A:PVP VA64 4 25 25% PVA-P 3.6 9/1 4 0.8 90A:PVA-P MeOH/ Water 5 25 10% HPMC E3 3.6 9/1 4 0.8 64 A:HPMC E3 MeOH/Water 6 25 25/65/10 PVP VA64 3 Acetone 4 1 91 A:PVP VA64: TPGS 7 2525/65/10 PVA-P 3 Acetone 4 1 94 A:PVA-P: TPGS 8 25 25/65/10 HPMC E3 29/1 4 1 25 A:HPMC E3: Methanol/ TPGS water 9 50 50% PVA-P 2 9/1 4 0.5100 A:PVA-P Acetone/ Water 10 50 50% HPMC E3 2 9/1 4 0.5 37 A:HPMC E3Methanol/ water 11 50 50/40/10 HPMC E3 2 9/1 4 0.5 52 A:HPMC E3:Methanol/ TPGS water 12 50 50/40/10 PVA-P 2 9/1 4 0.5 52 A:PVA-P:Acetone/ TPGS Water 13 50 50/40/10 PVP VA64 2 Acetone 4 0.5 94 A:PVPVA64: TPGS

TABLE 2 Spray-drying condition part B Drying SD SD SD Gas Solution InletOutlet Condenser Flow Soln Flow Atomization Entry Temp Temp Temp RateTemp Rate Pressure Nozzle No. [° C.] [° C.] [° C.] [g/min] [° C.][g/min] [PSI] Type 1 100 42 Single Pass 450 rt 29 110 Schlick 2.0 2 9442 Single Pass 450 rt 29 110 Schlick 2.0 3 90 42 Single Pass 450 rt 29110 Schlick 2.0 4 84 42 Single Pass 450 rt 29 110 Schlick 2.0 5 80 42Single Pass 450 rt 29 110 Schlick 2.0 6 105 42 Single Pass 450 rt 27 110Schlick 2.0 7 110 42 Single Pass 450 rt 27 110 Schlick 2.0 8 110 42Single Pass 450 rt 27 110 Schlick 2.0 9 108 42 Single Pass 450 rt 27 110Schlick 2.0 10 93 42 Single Pass 450 rt 27 110 Schlick 2.0 11 89 42Single Pass 450 rt 27 110 Schlick 2.0 12 84 42 Single Pass 450 rt 27 110Schlick 2.0 13 82 42 Single Pass 450 rt 27 110 Schlick 2.0

6.2 Summary of Compound 1 Animal Pharmacokinetics (PK) FormulationDevelopment Study

Compound 1 is a basic moiety, and has a pH-dependent solubility profile.Under a normal gastric pH range, the solubility and bioavailability isexpected to vary, leading to intra- and inter-patient PK variability.In-vitro and in-vivo evaluations of various Blend in Capsule (BIC)formulations were undertaken to minimize the pH dependence on the drugsubstance release.

A systematic formulation development was undertaken and resulted in theselection of three formulations (conventional formulation (F4-1 in Table11) (A), enhanced formulation (F15, Table 27) (B), and spray drieddispersion (Entry 1, Table 1-Table 2) (SDD) (C)) for evaluation in a dogPK study. Formulation A (conventional excipients) demonstrated thehighest variability in exposure, and a reduction of exposure atincreased gastric pH. Formulation C (SDD) showed the highest exposures,but had a modest reduction of exposure at increased gastric pH.

Formulation B was recommended as the basis for First In Human (FIH)formulation development. Combining an acidifier (e.g. citric acid) andsurfactant (e.g. sodium lauryl sulfate) provided a synergistic effect,by controlling local pH and enhancing drug solubility concurrently. Bothformulations B and C demonstrated the potential to mitigate gastric pHimpact. Formulation C utilized an amorphous SDD drug productintermediate.

6.3 Study 1 Prototype Formulations

Seven Compound 1 blends were prepared via the process listed in FIG. 1for drug release (dissolution) evaluation. The compositions of eachblend are shown in Table 3. The functional excipients were grouped intothree classes: acidifiers (tartaric acid, fumaric acid, and citricacid), precipitation inhibitors (PEG4000 and hydroxypropyl cellulose),and solubilizer (hydroxypropyl-beta-cyclodextrin).

TABLE 3 Compositions of Prototype Formulations (Study 1) (% w/w) F1-1F1-2 F1-3 F1-4 F1-5 F1-6 F1-7 Compound 1 26.7 citrate salt MCC PH10233.8 23.8 Mannitol 33.8 23.8 Tartaric acid 20 Fumaric acid 20 Citricacid 20 PEG4000 20 HPC 20 HP-β-CD 20 Kollidon CL 4.0 Colloidal SiO₂ 0.6Stearic acid 1.0 Total 100 Total weight 250 (mg) HPC = hydroxypropylcellulose; HP-β-CD = hydroxypropyl-beta-cyclodextrin; MCC =microcrystalline cellulose; PEG = polyethylene glycol.

Dissolution condition 1 (Table 4) was used to evaluate the release ofStudy 1 formulations (Section 6.3) in gelatin (FIG. 2) and HPMC (FIG. 3)capsule shells. Two stage dissolution condition 2 (Table 5) was alsoused to evaluate the release of Study 1 formulations in gelatin (FIG. 4)and HPMC (FIG. 5) capsule shells.

Dissolution Conditions 1

TABLE 4 Dissolution Method for Formulation Studies 1, 2 (FaSSIF)Dissolution Parameter Setting Apparatus USP Apparatus II (paddle)Dissolution media FaSSIF (pH 6.8) Media volume 900 mL Media temperature37° C. ± 0.5° C. RPM 75 rpm for first 60 minutes and infinity (250 rpmfor next 15 minutes) Sampling time 10, 15, 20, 30, 45, 60, and 75minutes Sample volume 1.5 mL (no media replacement) Flush volume 3.0 mLOffset Volume 2.0 mL Filter 10 μm UHMW PE Full Flow Filters AnalysisHPLC (UV 230 nm) RPM = revolutions per minute; USP = United StatesPharmacopeia. FaSSIF = Fasted State Simulated Intestinal Fluid

Dissolution Conditions 2

TABLE 5 Dissolution Method for Formulation Study 1 (Two Stage)Dissolution Parameter Setting Apparatus USP Apparatus II (paddle) Mediatemperature 37° C. ± 0.5° C. RPM 75 rpm Pull volume 1.5 mL (no mediareplacement) Flush volume 3.0 mL Offset Volume 2.0 mL Filter 10 μm UHMWPE Full Flow Filters Analysis HPLC (UV 230 nm) Dissolution media 1 0.1NHCl (pH~1.2, for gastric pH) Media volume 750 mL Sampling time 10, 15,20, 30, 45, and 60 Dissolution media 2 0.2M sodium phosphate tribasicadded to vessel. Adjust vessel pH to 6.80 ± 0.05 Media volume 250 mLSampling time 10, 15, 20, 30, 45, and 60 (after addition) RPM =revolutions per minute; USP = United States Pharmacopeia. FaSSIF =Fasted State Simulated Intestinal Fluid

Conclusions from Study 1 include the elimination of excipients (tartaricacid, hydroxypropyl cellulose, and HP-β-CD) from consideration due to anundemonstrated ability to mitigate gastric pH impact as determined bythe percentage of drug release.

Compound 1 precipitated during the buffer stage (pH 6.8) of the 2-stagedissolution in F1-2 gelatin capsules (tartaric acid).

F1-5 (PEG4000) percentage released was low in FaSSIF conditions.

F1-6 (HPC) percentage released was low in both FaSSIF and 2-stagedissolutions.

6.4 Study 2 Prototype Formulations

Six Compound 1 blends were prepared according to the process set forthin FIG. 1 for drug release (dissolution) evaluation. The compositions ofeach blend are shown in Table 6. The formulations were evaluated basedon the combinations of various functional excipients, i.e., surfactant(SLS), acidifier+precipitation inhibitor (fumaric acid or citricacid+PEG4000), acidifier+surfactant (citric acid+SLS), precipitationinhibitor+surfactant (PEG4000+SLS), acidifier+precipitationinhibitor+surfactant (citric acid+PEG4000+SLS). See Table 7.

TABLE 6 Compositions of Prototype Formulations (Study 2) (% w/w) F2-1F2-2 F2-3 F2-4 F2-5 F2-6 Compound 1 26.72 citrate salt MCC PH102 13.8413.84 28.84 18.84 18.84 8.84 Mannitol 13.84 13.84 28.84 18.84 18.84 8.84Fumaric acid 20 Citric acid 20 20 20 PEG4000 20 20 20 20 SLS 10 10 10 10Kollidon CL 4 0 Colloidal SiO₂ 0.6 Stearic acid 1.0 Total 100 Totalweight 250 (mg) MCC = microcrystalline cellulose; PEG = polyethyleneglycol; SLS = sodium lauryl sulfate.

In addition to the above six enhanced formulations, one formulationcontaining Compound 1 spray dried dispersion (SDD) blend was alsoprepared for drug release (dissolution) evaluation. The composition ofthe SDD formulation blend is shown in Table 7.

The SDD intermediate was prepared by the following procedures: Compound1 was dissolved in acetone in Vessel 1. HPMC and TPGS were dissolved inwater (heated to about 80° C.) in Vessel 2. Then the API in acetonesolution was added to HPMC/TPGS aqueous solution at a ratio of 4:6 andmixed into a clear and homogeneous solution. The solution was then fedinto Buchi B-290 under specified flow rate and inlet temperature. TheSDD intermediate powder was obtained in the collection vessel.

Ten grams of formulation blend was prepared according to the process setforth in FIG. 1 where Compound 1 was the SDD.

TABLE 7 Compositions of Prototype Formulation F2-7 in Study 2 (SDD)Component % w/w Weight per capsule (mg) Compound 1 20 135.1 mg SDDintermediate free base (37/53/10 Compound 1 free base/ HPMC 28.6HPMC/TPGS) TPGS 5.4 (54.0% w/w of the formulation) MCC PH102 20.2 50.45Mannitol 20.2 50.45 Kollidon CL 4.0 10 Colloidal SiO₂ 0.6 1.5 Stearicacid 1.0 2.5 Total 100 250 HPMC = hydroxypropyl methyl cellulose; MCC =microcrystalline cellulose; TPGS = Vitamin E (d-α-tocopheryl)polyethylene glycol 1000 succinate.

Dissolution condition 1 (Table 4) was used to evaluate the release ofStudy 2 formulations in gelatin (FIG. 6) and HPMC (FIG. 7) capsuleshells. Dissolution condition 3 (Table 8) was also used to evaluate therelease of Study 2 formulations in gelatin (FIG. 8) and HPMC (FIG. 9)capsule shells.

Among the formulations provided in Table 6, SLS alone (F2-3) andcombined with acid (F2-4) or polymer (F2-5) provide a superiorpercentage released as compared to other formulations, suggesting thatSLS is important for quick and immediate release of Compound 1.Combination of acid and polymer (F2-1, F2-2) does not offer synergisticeffects. Likewise, combination of SLS, acid, and polymer (F2-6) does notresult in the complete release of Compound 1 in gelatin capsules untilthe infinity time point, and has slightly slower release in HPMCcapsules. Therefore, PEG4000 does not improve the drug substance releaseand was therefore eliminated from further evaluation. SDD (F2-7) has aslower release profile, but completely releases prior to infinity.

Solubility of Compound 1 was determined in various percentages of sodiumlauryl sulfate (SLS). 0.03% SLS was selected as the media fordissolution condition 3. Samples were filtered using a 0.2 μm nylonsyringe filter, and analyzed by UPLC-UV utilizing the method parameterslisted in Table 9.

TABLE 8 Solubility of Compound 1 citrate in pH 6.5 phosphate buffer withSLS Solubility % SLS (mg salt/mL) 0.01 0.000 0.02 0.001 0.03 0.054 0.050.336 0.1 0.807 SLS = Sodium lauryl sulfate

TABLE 9 UPLC Method Conditions for Formulation Stability UPLC ParameterSetting Column Waters Acquity UPLC CSH C18 Dimensions 3.0 × 150 mmParticle size 1.7 μm Column temperature 45° C. Autosampler  5° C.temperature Mobile phases A: 0.01% TFA in Water B: AcetonitrileInjection volume 4 μL Flow rate 0.5 mL/minute Run time 26 minutesDetection wavelength 244 nm Time (min.) A % B % Gradient 0.0 90 10 1.090 10 14.0 50 50 20.0 10 90 21.0 10 90 21.1 90 10 26.0 90 10

6.5 Study Prototype Formulations

Study 3 included capsules prepared in Studies 1 and 2. F3-1 was F1-1from Study 1 filled into Size #00 white opaque gelatin capsules. F3-2was F1-4 from Study 1 filled into Size #00 white opaque gelatincapsules. F3-3 was F1-3 from Study 2 filled into Size #00 white opaquegelatin capsules. F3-4 was the pure SDD intermediate powder filled intoSize #00 white opaque gelatin capsules. Due to the low bulk density ofthe SDD intermediate, the maximum amount of 108.08 mg was filled intothe capsule shell, equivalent to 40 mg dose of Compound 1 free base.F3-5 was F2-7 from Study 2 compressed into a tablet. 200 mg of F3-5blend was compressed into a single tablet by a Carver Press using 2000lb compaction force and a standard flat-faced tooling. F3-6 had similarformulation components as F3-5, but with an increased level ofdisintegrant (Kollidon CL) at 10% instead of 4%. F3-6 was prepared inthe same way as F2-7 was prepared in Study 2. In order to compare itsdissolution profile with F3-4 and F3-5, F3-6 had 200 mg of blend filledinto Size #0 gelatin capsules to render the same dose strength of 40 mgas in F3-4 and F3-5. The compositions of each blend are shown in Table10.

TABLE 10 Compositions of prototype formulations (Study 3) (% w/w) F3-1F3-2 F3-3 F3-4 F3-5 F3-6 Compound 1 26.7 citrate salt Compound 1 10054.0 54.0 SDD¹ MCC PH102 33.8 23.8 28.84 20.2 17.2 Mannitol 33.8 23.828.84 20.2 17.2 Citric acid 20 SLS 10 Kollidon CL 4.0 4.0 10.0 ColloidalSiO₂ 0.6 0.6 0.6 Stearic acid 1.0 1.0 1.0 Total 100 Total weight 250108.08 200 200 (mg) Milligram 50 40 Compound 1 MCC = microcrystallinecellulose; SLS = sodium lauryl sulfate. F3-1 = F1-1 (Study 1); F3-2 =F1-4 (Study 1); F3-3 = F2-3 (Study 2); F3-5 (compressed into tablet) =F2-7 (Study 2 prepared as capsule) ¹SDD = 37/53/10% w/w/w Compound 1free base/HPMC/TPGS

As no major difference in dissolution performance was observed betweengelatin capsules and HPMC capsules of the same formulation in Study 1and Study 2, gelatin capsule was selected in the subsequent dissolutionevaluations. Dissolution condition 3 (Table 8) was used to evaluate therelease of Study 3 formulations (FIG. 10). Study 3 includes gelatincapsules prepared in Studies 1 and 2, and analyzed using dissolutionmethod 3, also used to evaluate Study 2 samples (FIG. 8).

F3-1 was prepared in Study 1, as F1-1. F3-2 was prepared in Study 1, asF1-4. F3-3 was prepared in Study 2, as F2-3. F3-4 contained only SDDintermediate filled into capsules. F3-5 was prepared in Study 2, as F2-7SDD, and was compressed into a tablet. F3-6 was a new SDD formulation(with increased disintegrant level) for Study 3.

F3-3 demonstrated the fastest drug release among all the sixformulations, confirming the conclusions from Study 2, i.e., SLS madekey contributions to the enhanced drug release profile. F3-2 (CitricAcid) demonstrated similar dissolution profile as that of F3-1(Conventional), implying that acid alone is not as effective as SLS toenhance the drug dissolution. The dissolution of the new SDD formulationF3-6 was improved as compared to the original SDD formulation, mostlikely due to the increased level of disintegrant in the formulation.However, it was still slower than F3-3, the enhanced formulation withSLS. F3-5 (SDD tablet) did not disintegrate, and the addition of a superdisintegrant (e.g., Ac-Di-Sol, croscarmellose sodium) would likely beadvantageous to drug release if a tablet formulation is investigated inthe future.

6.6 Study 4 Prototype Formulations

Study 4 evaluated acidifier, surfactant, and combinations of acidifierand surfactant. Seven Compound 1 blends were prepared according to theprocess set forth in FIG. 1 for drug release (dissolution) evaluation.The compositions of each blend are shown in Table 11. In this study,drug loadings were reduced from 26.7% (50 mg dose) to 13.36% (20 mgdose), and fill weight set to 200 mg in order to match the dose strengthrequired in the animal PK study.

TABLE 11 Compositions of prototype formulations (Study 4) (% w/w) F4-1F4-2 F4-3 F4-4 F4-5 F4-6 F4-7 Compound 1 13.36 citrate salt Compound 127.88 SDD¹ MCC PH102 40.52 35.52 35.52 38.02 33.02 33.02 33.26 Mannitol40.52 35.52 35.52 38.02 33.02 33.02 33.26 Citric acid 10 10 Fumaric acid10 10 SLS 5 5 5 Kollidon CL 4 Colloidal SiO₂ 0.6 Stearic acid 1 Total100 Total weight 200 (mg) MCC = microcrystalline cellulose; SLS = sodiumlauryl sulfate. ¹SDD = 37/53/10% w/w/w Compound 1 free base/HPMC/TPGS

Dissolution condition 3 (Table 8) was used to evaluate the release ofStudy 4 formulations in gelatin (FIG. 11) capsule shells.

Citric acid+SLS (F4-5) formulation was superior to the otherformulations in dissolution release, although the difference is notsignificant under the dissolution conditions used. The dose strength inStudy 4 was reduced from 50 mg per capsule used in Studies 1-3 to 20 mgper capsule in order to mimic the dose strength used in the subsequentanimal PK study.

Disintegration of SDD capsules (F4-7) is slow due to the high amount ofa polar HPMC in the spray dried intermediate.

F4-1 (conventional), F4-5 (enhanced: citric acid+SLS), and F4-7(enabled: SDD) are selected for a 1 month stability assessment (Section6.7) and evaluation in a dog PK Study (Section 6.8).

6.7 Preliminary Stability Results for Selected Capsule Formulations

Three selected formulations from Study 4 (Section 6.6) were evaluatedfor stability in open dish conditions. Assay and impurities wereevaluated for storage up to 1 month at 25° C./60% RH and 40° C./75% RH.Liquid Chromatography was used to evaluate the samples.

TABLE 12 HPLC Assay and Impurity Results for Selected Formulations RRTTotal Formulation Assay 0.36 0.41 0.84 0.89 0.95 0.96 0.98 1.04 1.10Impurities F4-1 Initial 85.7 ND ND ND <QL 0.51 ND 0.33 <QL 0.32 1.16 2W40° C./ 90.9 ND ND ND <QL 0.50 0.06 0.32 <QL 0.31 1.20 75% RH 1M 25° C./90.5 ND ND ND <QL 0.50 ND 0.32 <QL 0.32 1.14 60% RH 1M 40° C./ 90.0 NDND ND <QL 0.50 ND 0.32 <QL 0.32 1.14 75% RH F4-5 Initial 85.3 ND ND ND<QL 0.50 <QL 0.33 <QL 0.31 1.15 2W 40° C./ 87.8 ND ND <QL <QL 0.51 <QL0.33 <QL 0.31 1.15 75% RH 1M 25° C./ 88.2 <QL <QL ND <QL 0.51 ND 0.33<QL 0.31 1.15 60% RH 1M 40° C./ 71.9 <QL <QL ND <QL 0.51 ND 0.34 <QL0.30 1.15 75% RHF F4-7 Initial 95.5 ND 0.05 ND <QL 0.52 <QL 0.40 <QL0.31 1.28 2W 40° C./ 96.3 ND <QL ND 0.06 0.52 <QL 0.39 <QL 0.31 1.27 75%RH 1M 25° C./ 95.7 ND <QL ND <QL 0.52 ND 0.39 <QL 0.31 1.22 60% RH 1M40° C./ 93.3 ND <QL ND 0.08 0.52 ND 0.39 <QL 0.31 1.29 75% RH QL =quantitation limit = 0.05%; RRT = relative retention time. Shaded cells= changed observed; ND = not determined

No significant changes in assay were observed with the exception ofF4-5, 1 month 40° C./75% RH condition. As there was no change inimpurity profile, this result was likely related to capsule fill weightor the extraction procedure utilized in the assay method.

No significant changes (≥0.10%) were observed for impurities in any ofthe formulations. F4-5 had equivalent impurity values (none ≥QL). F4-1and F4-7 each had one impurity that grows >QL at the 40° C./75% RHcondition. The F4-1 impurity (RRT 0.96) result was not replicated in the1 month 40° C./75% RH sample, and was likely not sample related. TheF4-7 impurity (RRT 0.89) result did replicate in the 2 week and 1 month40° C./75% RH samples, and was likely sample related.

Acceptable stability was demonstrated for the three formulations whenstored for 1 month at 25° C./60% RH and 40° C./75% RH.

6.8 Dog PK Overview

Three formulations were tested in an animal PK Study to assess exposureand identify a lead first in human formulation.

In the study, 15 fasted male dogs (5/group) were administered two dosesof pentagastrin (0.006 mg/kg) to increase gastric acid secretion via theintramuscular route separated by a period of 60 minutes. A single 20 mgCompound 1 capsule (equivalent to 2 mg/kg) was administered 30 minutesfollowing the second pentagastrin dose.

Following a washout period of 1 week, all animals were fasted andadministered an oral dose of 40 mg famotidine to inhibit stomach acidproduction approximately 30 minutes prior to administration of a single20 mg Compound 1 capsule.

The gastric pH of each animal was measured prior to pretreatment, andprior to Compound 1 dosing. Blood samples were collected from eachanimal to obtain Compound 1 concentrations.

The formulations tested in the Study are described in Table 11, andsummarized below.

F4-1: Conventional formulation: 10% Compound 1

F4-5: Enhanced formulation: 10% Compound 1+10% citric acid+5% SLS

F4-7: Enabled formulation: spray-dried intermediate (10% active, 14.8%HPMC, 2.8% TPGS) with conventional excipients

Table 13 listed the gastric pH and PK results for the study. FIG. 12,FIG. 13 and FIG. 14 showed the plasma concentration of Compound 1 over a24 hour post dose time. FIG. 15 showed the comparison in AUC and C_(max)across the three different formulations in the two pH-controlled doggroups.

TABLE 13 Mean Pharmacokinetic Parameters Following a Single Oral CapsuleAdministration of Compound 1 to Male Beagle Dogs Pre- C_(max) AUC_(24h)Formulation treatment Gastric pH¹ T_(max) (hr)² (ng/mL) (ng*h/mL) F1(Standard) Pentagastrin 3.4 (2.2-5.0) 2.0 (1.0-4.0) 492 ± 160 3520 ±1610 Famotidine 7.5 (7.1-7.9) 2.0 (1.0-4.0) 292 ± 80.4 2160 ± 726 F5(Enhanced) Pentagastrin 2.7 (2.2-3.8) 4.0 (2.0-4.0) 385 ± 65.9 2610 ±926 Famotidine 7.5 (7.3-7.7) 2.0 (1.0-4.0) 382 ± 84.6 2610 ± 936 F7(Enabled) Pentagastrin 2.4 (1.9-3.2) 2.0 (2.0) 686 ± 131 3610 ± 1070Famotidine 7.1 (5.5-7.7) 2.0 (2.0-4.0) 475 ± 112 3370 ± 877 AUC_(24h) =area under the plasma concentration-time curve from time 0 to 24 hourspost-dose; C_(max) = maximum plasma concentration; T_(max) = time tomaximum plasma concentration (C_(max)) ¹Gastric pH measured prior toCompound 1 administration. Average for each group and range reported.²T_(max) values are reported as median (range), while other parametersare reported as mean ± SD (n = 5).

The conventional formulation (F4-1) exhibited the highest variability inexposure between two pH treatment groups, and is not proposed as the FIHformulation.

The enabled formulation (F4-7) containing the SDD demonstrated higherC_(max) and AUC than the enhanced formulation (F4-5), and demonstratedless variability in comparison to F4-1.

The enhanced formulation (F4-5) containing the crystalline APIdemonstrated the most consistent C_(max) and AUC values at both low andhigh gastric pH conditions. The average C_(max) and AUC values wereapproximately equivalent to F4-1, and the average AUC was 75% andC_(max) was approximately 65% of the F4-7 results.

The enhanced formulation was selected for the FIH formulation due tomore consistent PK results over the pH range studied and the eliminationof the manufacture of the spray dried dispersion (SDD).

6.9 Conclusions

Clinical exposure to Compound 1 could vary based upon patient stomachpH. A systematic formulation development was undertaken to minimize theimpact of gastric pH variability on exposure, thereby reducing intra-and inter-patient PK variability.

An enhanced formulation containing citric acid and sodium lauryl sulfatedemonstrated minimal variability in exposure upon gastric pH change inan animal PK study.

The enabled formulation containing the SDD had the highest overallexposure, and showed moderate exposure variability with gastric pH.Given the dose range of interest in clinical studies, it is the exposurevariability rather than the absolute exposure that is of most interest.The formulation required an additional spray drying step in themanufacturing process and offered little advantage over the enhancedformulation.

6.10 Summary of Compound 1 First in Human Formulation (FIH) DevelopmentStudy

Compound 1 is intended for the treatment of colorectal cancer. A bigportion of the patient population who take proton pump inhibitors (PPI)may exhibit higher gastric pH than normal patients. Compound 1 has a pHdependent solubility profile, resulting in potential intra- andinter-patient PK variability. Blend in capsule formulation developmentwas undertaken to minimize the pH dependence on the drug substancerelease.

An enhanced formulation combining an acidifier (citric acid) andsurfactant (sodium lauryl sulfate) for control of local pH and enhancingdrug solubility exhibited minimal change in Compound 1 exposures in dogspretreated with pentagastrin (increases gastric acid secretion) orfamotidine (inhibits stomach acid production). This formulation was thestarting composition for FIH formulation development studies.

Systematic development and evaluation (stability and dissolution) offormulations containing conventional excipients, acidifiers,surfactants, antioxidants, and lubricants was performed. The combinationof surfactant and acidifier improved the chemical stability over justthe surfactant, with fumaric acid having better chemical stability thancitric acid. Formulations containing citric acid (low dose in gelatincapsules) showed capsule shell breakage at accelerated stabilitycondition. Therefore, fumaric acid was selected as the acidifier in lieuof citric acid in the formulation. Based on the accelerated stabilityassessment program (ASAP) data, the FIH formulation had a projectedshelf life of three years at room temperature, irrespective of packagingand desiccant addition.

The addition of surfactant and acidifier to a conventional formulationreduced the differences in dissolution release profile across thephysiological pH range, with the pH 6.8 buffer system having the fastestrelease. Inter capsule dissolution release variability was noted informulations containing fumaric acid and sodium laureth sulfate filledinto HPMC capsules shells. It should be noted that the dissolutionvariability was drastically minimized when the same formulation wasfilled into Gelatin capsule shells. Thus, Gelatin capsule shells wererecommended for this formulation.

The FIH formulations had been successfully scaled to 2 kg. The clinicaldose range is 1 to 150 mg, and a common blend may not cover the entirerange. Additionally, the needle particle morphology of the drugsubstance resulted in poor flow for high drug load blends. Initially,three capsule strengths (1, 5, and 25 mg) were targeted, however inbalancing drug load for a passable flow, and capsule size, the highestcapsule strength was reduced to 20 mg. Blend flow, stratified capsulehomogeneity, and sticking on the tamping pins may be manufacturingchallenges, and were monitored during development.

6.11 Introduction

The objective of the Compound 1 first in human (FIH) development programwas to create a phase-appropriate immediate-release, solid oral dosageform and manufacturing process that consistently meets safety andefficacy requirements of the Quality Target Product Profile (QTPP)throughout the product's intended shelf life.

A prototype blend in capsule (BIC) formulation was selected based onprevious animal PK studies as a starting point for FIH formulationdevelopment. Information from an initial Target Product Profile (TPP)was used as the design basis for the drug product, which is summarizedin Table 14.

TABLE 14 Target Product Profile (Initial for FIH) Dosage Form Solid oral(formulated blend in capsule) Dose Target range 1 to 150 mg, obtainedfrom multiple dosage form strengths Storage Room temperature

Table 15 represents a contemporary form of the Quality Target ProductProfile, and lists the type of information that was used to providefurther guidance during FIH formulation development.

TABLE 15 Quality Target Product Profile (Initial for FIH)Delivery/Release Appropriate dissolution profile for an immediaterelease Characteristics oral solid dosage form Safety and Assay: 90 to110% of label claim Efficacy Content Uniformity: Meets USP <905>Attributes Related substances (degradants): Conform to proposedspecifications Microbial Quality: Meets USP <61> and USP <62> PatientCapsule no larger than size #0 Compliance Shelf Life ≥18 months at roomtemperature storage conditions

6.12 Formulation Development and Evaluation

Based upon dog PK study, an enhanced formulation blend (F4-5) containingan acidifier and a surfactant in gelatin capsules (Table 16) wasselected as the base formulation for FIH formulation development. Aone-month stability study of F4-5 showed no change in the impurityprofile after storage at 25° C./60% RH and 40° C./75% RH.

TABLE 16 Composition of Prototype Dog PK Formulation Formulation F5Component (% w/w) Compound 1 13.36 Avicel PH102 33.02 Mannitol 33.02Citric acid 10 Sodium lauryl sulfate 5 Kollidon CL 4 Colloidal silicondioxide 0.6 Stearic acid 1 Total percent 100 Total weight (mg) 200Capsule strength (mg) 20

6.13 Selection of Dose Strengths and Drug Loadings

The projected clinical dose range is 1 to 150 mg, and three dosage formstrengths (1, 5, and 25 mg) were targeted.

A preliminary evaluation of several drug loadings was conducted based onthe bulk density and potential dosage unit size of the resulting blends(Table 17). Given the lower limit of capsule fill weight of 75 mg fromthe processibility perspective, the lowest drug loading was determinedto be 1.8% for a dose strength of 1 mg. The desired capsule size is size1 or below from patient compliance perspective. Therefore, the “commonblend” approach was deemed not applicable for dry blending process. As aresult, the drug loadings of 6.8% and 22.5% were selected for a dosestrength of 5 mg and 25 mg respectively. The low drug loading of 1.800and the high drug loading of 22.5%0 were evaluated from the chemicalstability perspective and the dissolution perspective, respectively, insubsequent formulation development studies.

TABLE 17 Formulation and Dosage Form Characteristics Drug Bulk Targetfill Max fill % of Strength loading density weight Capsule weightcapsule (mg) (%) (g/mL) (mg) size (mg) volume 1 1.8 0.44 75 4 92 82 51.8 0.44 375 00 400 94 5 6.8 0.41 100 3 123 81 25 13.5 0.32 250 00 29186 25 22.5 0.30 150 1el 162 93

6.14 Evaluation of Formulation Stability and Dissolution

The base formulation (Table 16) selected from the animal PK study wasoptimized in order to achieve the desired formulation stability anddissolution profile. Experiments were performed to determine theappropriate types and levels of excipients to incorporate into the FIHformulation.

6.15 Impact of Excipient Level on Dissolution

10% citric acid and 5% SLS were used in the base formulation. In orderto optimize the level of excipients, six 25 mg formulations in gelatincapsules: F18-1 (conventional) as the control, and varying levels of anacidifier (citric acid—CA) and surfactant (sodium lauryl sulfate—SLS)were prepared (Table 18). Dissolution of each formulation in pH6.5FaSSIF media was evaluated and the results are listed in Table 19 andplotted in FIG. 16.

TABLE 18 Formulation F18-1-F18-6 Varying Acidifier and Surfactant LevelsFormulation (% w/w) Component F18-1 F18-2 F18-3 F18-4 F18-5 F18-6Compound 1 22.5 Aerosil 200 0.6 Crospovidone 4 Magnesium stearate 1Citric acid, 0 0 0 5 10 5 anhydrous Sodium lauryl 0 1 2.5 0 5 2.5sulfate Avicel PH 102 18.0 17.7 17.4 16.7 14.2 16.1 Mannitol 54.0 53.252.1 50.2 42.7 48.3

TABLE 19 Dissolution comparison F18-1-F18-6 Baskets, 100 RPM, pH 6.5FaSSIF 10 min 15 min 20 min 30 min 45 min 60 min 75 min % Dissolved(Normalized to 100% at Infinity) in FaSSIF F1 16.0 42.9 63.0 75.1 83.188.7 100.0 F2 63.8 82.2 87.4 91.0 94.2 96.3 100.0 F3 64.0 82.2 86.7 90.693.5 95.9 100.0 F4 53.5 75.9 83.3 89.2 93.6 96.3 100.0 F5 65.4 86.6 90.893.7 95.5 96.4 100.0 F6 69.1 88.5 92.8 95.5 96.7 97.7 100.0 % Dissolved(as is) in FaSSIF F1 13.7 36.8 54.0 64.4 71.2 76.0 85.7 F2 57.0 73.277.3 80.8 83.4 85.4 89.1 F3 57.7 74.4 79.0 82.4 85.2 87.1 90.5 F4 46.766.3 72.7 77.8 81.7 84.0 87.3 F5 60.9 80.7 84.6 87.3 89.0 89.8 93.2 F660.9 78.0 81.8 84.1 85.3 86.2 88.2

Dissolution conditions: 900 mL FaSSIF, apparatus I (basket), 100 rpm.FaSSIF=fasted-state simulated intestinal fluid (pH 6.5 and contains 3 mMSodium Taurocholate, 0.75 mM Lecithin).

The slowest dissolution was the conventional formulation (F18-1) withoutacidifier or surfactant. F18-6 (5% CA and 2.5% SLS) had the fastestrelease profile, slightly faster than F18-5 (5% CA and 5% SLS). Bothshowed faster release than F18-2 (1% SLS), F18-3 (2.5% SLS), and F18-4(5% CA), indicating a synergistic effect of the acidifier in combinationwith the surfactant on drug dissolution. The release profiles with thesurfactant level of 1% was comparable to that with 5% SLS. Therefore, abase formulation containing 5% CA and 1% SLS was selected for subsequentformulation development studies.

6.16 Stability Studies with Various Diluents, Acidifiers, Antioxidants,and Lubricants

Stability studies evaluating the various components of the formulationwere studied.

Citric acid (CA) and stearic acid (SA) showed degradation in theexcipient compatibility study. Therefore, alternative acidifiers andlubricants were evaluated to mitigate potential stability risks.Formulation F20-1 (conventional) is the control; and 8 additionalformulations were prepared. F20-2 contains CA+SLS; F20-3 and F20-4include either butylated hydroxytoluene (BHT) or sodium metabisulfite(SMB) as an antioxidant; F20-5 and F20-6 contain either CA or SLS; F20-7includes an alternative acidifier (fumaric acid); F20-8 and F20-9include an alternative lubricant stearic acid or sodium stearyl fumarate(SA or SSF).

Formulation compositions are listed in Table 20. Formulations wereencapsulated into hard gelatin capsules. Capsules were packaged inheat-induction sealed HDPE bottles (7 count per bottle) and staged onstability at 50° C./75% RH.

TABLE 20 1 mg Formulation Component Screening Composition and FunctionFormulation (% w/w) Component F20-1 F20-2 F20-3 F20-4 F20-5 F20-6 F20-7F20-8 F20-9 Compound 1 1.84 Disintegrant: Crospovidone 4 Glidant:Aerosil 200 0.6 Diluent: Avicel PH102 23.14 21.64 21.62 21.62 21.8922.89 21.89 21.64 21.64 Diluent: Mannitol 69.42 64.92 64.85 64.85 65.6768.67 65.67 64.92 64.92 Solubilizer: SLS 0 1 1 1 0 1 0 1 1 AcidifierCitric acid 0 5 5 5 5 0 0 5 5 Fumaric acid 0 0 0 0 0 0 5 0 0 AntioxidantButylated hydroxytoluene 0 0 0.1 0 0 0 0 0 0 Sodium metabisulfite 0 0 00.1 0 0 0 0 0 Lubricant Magnesium stearate 1 1 1 1 1 1 1 0 0 Stearicacid 0 0 0 0 0 0 0 1 0 Sodium stearyl fumarate 0 0 0 0 0 0 0 0 1 SLS =sodium lauryl sulfate.

6.17 Assessment of Compound 1 Form Conversion

Formulations were assessed by X-ray powder diffraction (XRPD) initiallyand after 1 month storage at 50° C./75% RH to evaluate for Compound 1polymorphic form conversion or disproportionation of the citrate salt(Table 21). Disappearance of drug peaks at the lower diffraction angleswas observed, but a form change from Form B to Form A or saltdisproportionation is challenging to detect at the 1.84% drug loadinglevel. XRPD was also performed on higher DL conventional and enhancedformulations (22% DL). No evidence was observed of form change or saltdisproportionation.

TABLE 21 Summary of XRPD Results for F1-F9 Sample Initial 1 month (50°C./75% RH) 8204-014-F1 Crystalline No Major Changes (peak at 5.5° 2θdisappears) 8204-014-F2 Crystalline Drug peaks disappear 8204-014-F3Crystalline Drug peaks disappear 8204-014-F4 Crystalline Drug peaksdisappear and peak at 26.1° 2θ diminishes significantly 8204-014-F5Crystalline Drug peaks disappear 8204-014-F6 Crystalline Drug peaksdisappear 8204-014-F7 Crystalline Peaks at 5.5 and 28.8° 2θ disappear8204-014-F8 Crystalline Drug peaks disappear 8204-014-F9 CrystallineDrug peaks disappear Note: Major Compound 1 Form B peaks that arereadily distinguishable are three peaks between 4° and 7° 2θ.

6.18 Capsule Appearance

Capsule appearance was evaluated after 1 month storage at 50° C./75% RH.All the formulations containing CA showed significant capsule shellbreakage. Citric acid is hygroscopic, and it was suspected that themoisture uptake results in brittleness of capsule shells.

6.19 Chemical stability

Degradation (RRT 0.88) was only observed for formulations F20-1, F20-6,F20-7 after 1 month storage at 50° C./75% RH (Table 22). Theseformulations do not contain citric acid. RRT 0.88 degradation productformula by mass spectrometry is C₂₄H₂₆C₃N₇O₂. This corresponds to a lossof hydrogen fluoride. This impurity has been observed in alkalineconditions.

No degradation was observed in formulation (F20-2).

TABLE 22 Stability % Impurity Results for 1 mg Formulations 1-9 TimeInitial % impurity Formulation F20-1 F20-2 F20-3 F20-4 F20-5 F20-6 F20-7F20-8 F20-9 RRT 0.88 Des-F 91516 0.52 0.51 0.52 0.5 0.52 0.52 0.51 0.510.51 CC-20048 0.36 0.36 0.36 0.36 0.36 0.36 0.36 0.36 0.36 RRT 1.10 0.13Bis-F 91516 0.32 0.32 0.32 0.32 0.32 0.32 0.32 0.32 0.32 Total Imps 1.21.2 1.2 1.3 1.2 1.2 1.2 1.2 1.2 Time 1 month at 50° C./75% RHFormulation F1 F2 F3 F4 F5 F6 F7 F8 F9 RRT 0.88 0.15 0.31 0.09 Des-F91516 0.52 0.52 0.52 0.52 0.52 0.52 0.52 0.52 0.52 CC-20048 0.36 0.370.36 0.36 0.36 0.37 0.36 0.36 0.36 RRT 1.10 Bis-F 91516 0.32 0.32 0.320.33 0.33 0.32 0.33 0.32 0.32 Total Imps 1.4 1.2 1.2 1.2 1.2 1.5 1.3 1.21.2 Note: Only peaks ≥ quantitation level reported.

6.20 Stability Studies with Two Acidifiers and HPMC/Gelatin CapsuleShells

Five 1 mg formulations encapsulated in gelatin or hydroxypropylmethylcellulose (PMC) capsule shells were manufactured and evaluated forstability. F20-2, F20-5, F20-6, and F20-7 were previously described inTable 20: Anew formulation, F23-14, contains the acidifier fumaric acid(FA), which was substituted for citric acid. The formulations are listedin Table 23.

TABLE 23 Composition of 1 mg Formulations Formulation (% w/w) ComponentF20-2 F20-5 F20-6 F20-7 F23-14 Compound 1 1.84 Crospovidone 4  Aerosil200 0.6 Magnesium stearate 1   Avicel PH102 21.64 21.89 22.89 21.8921.64 Mannitol 64.92 65.67 68.67 65.67 64.92 Acidifier Citric acid 5 5 00 0 Fumaric acid 0 0 0 5 5 Sodium lauryl sulfate 1 0 1 0 1

Capsule appearance and formation of degradation product RRT 0.88 weremonitored for stability, and results up to 3 months are provide in Table24.

Formulations F20-2 and F20-5 containing citric acid and encapsulated ingelatin capsule shells showed capsule brittleness after 3 months at 40°C./75% RH and capsule breakage after 1 month at 50° C./75% RH. No changein appearance was noted for any other formulation of capsule shell.

Formulation F6 containing SLS and no acidifier had the highest level ofRRT 0.88 degradation product. Addition of acidifier improved thechemical stability. F23-14 (FA+SLS) formulation showed lower levels ofRRT 0.88 than F20-2 (CA+SLS) formulation.

F23-14 (FA+SLS) and F20-7 (FA) in HPMC and gelatin shells, and F20-5(CA) in HPMC shells showed acceptable accelerated stability results.

TABLE 24 Stability Results for 1 mg Formulations Capsule appearance %RRT 0.88 degradation product 40° C./ 50° C./ 40° C./75% RH 50° C./75% RH75% RH 75% RH Formulation Shell 1 Mo 3 Mo 1 Mo 2 Mo 3 Mo 1 Mo F2 HPMC0.02 0.06 0.11 0.17 No Change No Change (CA + SLS) Gelatin 0 0.04 0 NTBrittle Breakage F5 HPMC 0 0.03 0.05 0.08 No Change No Change (CA)Gelatin 0 0.03 0 NT Brittle Breakage F6 HPMC 0.04 0.17 0.2 0.40 NoChange No Change (SLS) Gelatin 0.03 0.13 0.31 NT No Change No Change F7HPMC 0 0 0 0.02 No Change No Change (FA) Gelatin 0 0 0.09 NT No ChangeNo Change F14 HPMC 0 0 0.02 0.03 No Change No Change (FA + SLS) Gelatin0 0 0.03 0.03 No Change No Change CA = citric acid; FA = fumaric acid;NT = not tested; SLS = sodium lauryl sulfate.

An accelerated stability assessment program (ASAP) was performed onformulations blends F23-14 (FA+SLS) and F20-5 (CA) (Table 25).Formulation F23-14 demonstrated lower levels of RRT 0.88 degradationproduct throughout study.

TABLE 25 ASAP Stability Conditions and RRT 0.88 Degradation ProductLevels Time Storage % RRT 0.88 Sample (Days) Condition F5—CA F14—FA +SLS 1 0 Initial ND ND 2 0 ND ND 3 8 52° C./60% RH ND ND 4 14 0.02 ND 5 760° C./11% RH 0.01 ND 6 14 0.01 ND 7 1 70° C./28% RH ND ND 8 11 0.130.02 9 1 69° C./81% RH 0.04 0.02 10 2 0.06 0.05 11 1  79° C./9% RH 0.02ND 12 7 0.14 0.04 13 3 49° C./85% RH ND ND 14 14 0.01 0.02 15 1 79°C./49% RH 0.10 0.05 16 2 0.18 0.07

A humidity corrected Arrhenius equation (i.e., ASAP Prime version 4.0.1)was used to assess the stability results. Activation energy (Ea) and themoisture sensitivity (B) to degradation were assessed and are listed inTable 26. B term demonstrated that the formulations have a low tomoderate sensitivity to moisture mediated degradation. The activationenergy of both formulations were equivalent to lower than other testedformulations (average 27 kcal/mole for 69 formulations tested), and incombination should lead to a stable dosage form. This is borne out withthe high probability of meeting proposed shelf life under variousscenarios. Based on the model prediction, F23-14 was expected todemonstrate long-term stability at 25° C./60% RH, with or withoutdesiccant.

TABLE 26 Degradation Kinetics and Shelf Life Probability F23-14Parameter F20-5 (CA) (FA + SLS) Activation Energy (E_(a), kcal/mol)^(a)36.8 kcal/mol 27.2 kcal/mol Moisture Sensitivity Coefficient (B)^(b)0.025 0.032 Correlation Coefficient (R²) 0.987 0.918 Probability ofpassing specification 1.0% Spec at 25° C./60% RH, 3 years 100.00 99.951.0% Spec at 40° C./75% RH, 6 months 100.00 100.00 1.0% Spec at 25°C./60% RH, 3 years, 100.00 99.99 1.0 g of Desiccant 1.0% Spec at 40°C./75% RH, 6 months, 100.00 100.00 1.0 g of Desiccant 0.20% Spec at 25°C./60% RH, 3 years 99.90 96.86^(d) 0.20% Spec at 40° C./75% RH, 6 months99.97 96.24 0.20% Spec at 25° C./60% RH, 3 years, 99.67 99.36 1.0 g ofDesiccant 0.20% Spec at 40° C./75% RH, 6 months, 99.98 99.93 1.0 g ofDesiccant CA = citric acid; FA = Fumaric acid; SLS = sodium laurylsulfate ^(a)Average activation energy of an impurity is 27 kcal/mol^(b)Average moisture sensitivity coefficient of an impurity is 0.034^(c)Probability of passing specification ^(d)Decrease in probability ofmeeting specification is likely caused by poor model fit (too littledegradation during study to appropriately model the data)

Simulations assumed 7 count in a 100 cc HDPE bottle which was heatinduction sealed.

6.21 Dissolution of High Drug Load Formulations F10, F12, F13, F15, F16

Five high drug loading (23%) 25 mg formulations were prepared and filledinto gelatin capsules. F27-10 (CA+SLS) and F27-11 (conventional) werethe controls; and 4 additional formulations were prepared. F27-12 andF27-16 contained either CA or FA; F27-13 contained sodium laurylsulfate; F27-15 was the same as F10, with FA in place of CA. Formulationcompositions are listed in Table 27. The capsules were tested usingapparatus I (baskets) at 100 RPM.

TABLE 27 Compositions of 25 mg Formulations Formulation (% w/w)Component F27-10 F27-11 F27-12 F27-13 F27-15 F27-16 API 23.02Crospovidone 4 Aerosil 200 0.6 Magnesium 1 Stearate Avicel PH102 16.3517.85 16.60 17.60 16.35 16.60 Mannitol 49.04 53.54 49.79 52.79 49.0449.79 Citric acid 5 0 5 0 0 0 SLS 1 0 0 1 1 0 Fumaric acid 0 0 0 0 5 5Fill Weight (mg) 150 SLS = sodium lauryl sulfate

The release profiles of each formulation in 0.1 N HCl (FIG. 18), pH 4.5acetate buffer (50 mM) (FIG. 19), and pH 6.8 phosphate buffer (50 mM)(FIG. 20) are provided.

At low pH, Compound 1 was soluble (˜1.7 mg/mL). The formulations weregrouped, with the conventional (F27-11) releasing slightly faster thanformulations containing just FA (F27-16) or CA (F27-12). Theformulations containing SLS were similarly grouped with F27-10 (CA+SLS)releasing faster than F27-13 (SLS), which had a similar release profileto F27-15 (FA+SLS).

At pH 4.5, Compound 1 (pKa ˜5.1) was less soluble (0.25 mg/mL) than inmore acidic media. The formulations were grouped, with the enhancedformulations releasing faster than the conventional formulation. For theenhanced formulations, F27-10 (CA+SLS) released faster than F27-15(FA+SLS) and F27-13 (SLS), which released slightly faster than the FA(F27-16) and CA (F27-12) formulations.

At pH 6.8, Compound 1 had low solubility (0.002 mg/mL at pH 7.3). Theformulations were grouped in the same order as pH 4.5, however thespacing between the groups was larger. For the enhanced formulations,F27-10 (CA+SLS) released faster than F27-15 (FA+SLS) and F27-13 (SLS),which released faster than FA (F27-16) and CA (F27-12) formulations.

SLS containing formulations had the slowest release rate at low pH, andthe fastest release at pH 6.8. The release profiles were slightly fasterfor the SLS formulations at pH 4.5 when compared to low pH media. SLS isanionic and Compound 1 (pKa 5.1) is cationic in acidic media. It ispossible that an ionic interaction is occurring between SLS and the drugsubstance, creating a neutral species that suppresses the release ratefor these formulations.

Dissolution profiles of the 25 mg enhanced formulation (FA+SLS) (F27-15,Table 27) with apparatus I at 100 RPM in 0.1N HCl, pH 4.5 acetate bufferand pH 6.8 phosphate buffer is shown in FIG. 21.

The same dissolution conditions were used to evaluate a conventionalformulation for comparison, and the profiles are shown in FIG. 22. Acomparison of the profiles showed that the enhanced FIH formulation hada consistent release profile, and had less variability as a function ofpH compared to a conventional formulation.

At pH 4.5 and 6.8, the non-SLS containing formulations had a much slowerrelease than at low pH. The combination of acidifier and SLS providedthe fastest dissolution at medium and neutral pH and moderatedissolution at low pH.

6.22 Evaluation of Capsule Shell Composition on Dissolution

Formulation F27-15 in Table 27 encapsulated in HPMC and gelatin shellswere evaluated at pH 6.8, with and without the addition of 0.05% SLSinto the dissolution media.

At neutral pH, high variability in dissolution of Formulation F27-15 inTable 27 was observed in FA+SLS formulation with HPMC capsule shells (25mg strength) (FIG. 23), but not with gelatin capsule shells (FIG. 24).

0.5% SLS was added to the dissolution media, and high dissolutionvariability of Formulation F27-15 in Table 27 continued to be observedin FA+SLS formulation with HPMC capsule shells (FIG. 25), but not withgelatin capsule shells (FIG. 26).

The SLS only formulation (F27-13 in Table 27) behaved similarly (HPMC:FIG. 27, gelatin: FIG. 28), however this phenomenon was not observed inCA+SLS formulation (F27-10 in Table 27) in HPMC (FIG. 29).

It was suspected that interaction between FA, SLS, and HPMC capsuleshells resulted in the varied drug release.

At the end of dissolution, HPMC capsules retained gel-like, lumpyresidual solids in the basket. See FIG. 30. If these gelatinousmaterials entrapped Compound 1, variable dissolution profiles couldresult.

6.23 Results

Based on the stability and dissolution result, Formulation F27-15 inTable 27 which contained 5% fumaric acid and 1% SLS and filled in hardgelatin capsule shells had the best overall stability and dissolutioncharacteristics.

6.24 Process Development and Evaluation

The physical properties of the drug substance such as particle size,shape, and surface characteristics can play a role in themanufacturability of the formulation. Compound 1 (citrate salt form B)crystallized in a needle shape.

Needle-like particle shapes have poor powder flow and low densities.Compound 1 had a bulk density of 0.2 g/mL and a tap density 0.38 g/mL.Reduced drug loadings (dilution of the poor flow component) improvedflow characteristics of the resultant blend. The flowability of sixconventional formulations has been listed in Table 28.

TABLE 28 Flowability Assessment of Six Prototype Formulation BlendsFormulation (% w/w) Component F28-1 F28-2 F28-3 F28-4 F28-5 F28-6Compound 1 1.8 6.74 13.48 22.46 22.46 22.46 Avicel PH102 46.3 43.8340.46 35.97 23.98 23.98 Mannitol 46.3 43.83 40.46 35.97 47.96 Lactose47.96 Crospovidone 4 Aerosil 200 0.6 Magnesium 1 Stearate FFC 11.6 5.93.2 2.5 2.5 2.5 FFC = flow function coefficient.

Flow function coefficients (FFC) were measured by ring shear. FFC valuesgreater than 5 had good flow properties. Formulations F28-1 and F28-2were assessed to have good flow properties. The FFC value is directlyrelated to drug loading (F28-1<F28-2<F28-3<F28-4-F28-6). Changing theratio of Avicel to Mannitol (F28-4 vs. F28-5) or replacing mannitol withlactose (F28-5 vs. F28-6) did not impact flowability.

6.25 600 g Manufacturing Trial 1

Five formulations of various drug loadings were developed (Table 29) tocover the anticipated FIH dose range.

For a 1 mg dose, and a 75 mg weight, the resulting drug load wascalculated to be 1.8%. For the 5 mg dose, a fill weight of 100 mgresulted in a drug loading of 6.9%. For the 25 mg dose, a fill weight of150 mg resulted in a drug load of 23%. Based on the poor flow propertiesfor high drug loading formulations (FFC=2.5, Table 28) a lower DL(13.81%, corresponding to 250 mg fill weight) was also evaluated. A 20mg dose was also developed, and a fill weight of 250 mg resulted in adrug loading of 11%

TABLE 29 Formulation Composition and Characterization Formulation (%w/w) Component F29-1 F29-2 F29-3 F29-4 F29-5 Compound 1 1.84 23.02 6.9113.81 11.05 Avicel PH102 21.64 16.35 20.37 18.65 19.34 Mannitol 64.9249.04 61.12 55.94 58.01 Citric acid 5 SLS 1 Crospovidone 4 Aerosil 2000.6 Magnesium 1 Stearate SLS = sodium lauryl sulfate. NB Ref: 8204-015.

Five 600 g trial formulations were manufactured with the process flowshown in FIG. 31.

The 5 formulations covered drug loadings of 1.8-23.0% and 1-25 mgstrengths. The bulk and tap densities for each formulation are includedin Table 30.

TABLE 30 Formulation Characterization Characteristics F29-1 F29-2 F29-3F29-4 F29-5 Dose Strength (mg) 1^(a) 25^(a) 5^(a) 25^(a) 20^(a) DrugLoading (%) 1.8 23.0 6.9 13.8 11.0 Fill Weight (mg) 75 150 100 250 250Bulk Density 0.46 0.28 0.44 0.34 0.41 (g/mL) Tap Density (g/mL) 0.590.55 0.61 0.58 0.61 ^(a)Based on free-base. 1.0 mg Compound 1(free-base) was equivalent to 1.34 mg Compound 1 (citrate salt). Drugsubstance lot potency factor for these experiments was (0.725 or1/1.38).

The CU results of F29-1, F29-3, and F29-5 are shown in Table 31. Thefailed CU data suggest that manual sieving used in the process may notbe an effective way to deagglomerate blends, resulting in blendheterogeneity. Additional trials were conducted with an improved process(substitution of a Comil for manual sieve) and were described in thenext section.

TABLE 31 Stratified CU Results F29-1, F29-3 and F29-5 F29-1 (1 mg), 75mg fill, Size #4 F29-3 (5 mg), 100 mg fill, Size #4 Beginning Middle EndBeginning Middle End Capsule % Capsule % Capsule % Capsule % Capsule %Capsule % Weight LC Weight LC Weight LC Weight LC Weight LC Weight LCAverage 111.3 90.4 110.8 95.1 110.3 93.8 144.4 106.5 149.9 110.8 146.9108.6 STD 1.0 4.5 0.9 5.2 0.5 5.7 3.8 4.8 2.1 2.3 3.2 2.9 AV 19.0 15.918.3 16.4 14.9 14.1 Pass L1 No No No No Yes Yes F29-5 (20 mg), 250 mgfill, Size #1 Average 351.2 99.4 353.8 104.1 343.3 99.7 STD 7.8 4.1 14.45.6 24.6 10.4 AV 9.8 16.1 25.0 Pass L1 Yes No Mo

The 25 mg formulations with drug loading of 13.8% and 23% had poor flowand the encapsulation process was paused several times. A spatula orhammer was used to facilitate powder flow in the feeding hopper. It wasconcluded that such high drug loading was not suitable for a dryblending process.

When the drug loading was reduced to 11%, the flow was improved.Therefore, the highest dose strength was reduced from an initial targetof 25 mg to 20 mg to ensure a good processability and an appropriatecapsule size.

6.26 600 g Manufacturing Trial 2

Based on Trial 1 results, two additional 600 g batches weremanufactured, one of formulation F29-1 (low drug loading at 1.8%) andthe second of formulation F29-5 (high drug loading at 11%) (Table 29).In order to improve the blend uniformity and be more representative ofthe scale-up process, a Quadro Comil U3 was used for deagglomeration andBosch GKF 702 was used for encapsulation (FIG. 32). The encapsulationparameters for both batches are listed in Table 32.

TABLE 32 Encapsulation Setup Parameters Parameter F29-1 (1 mg) F29-5 (20mg) Dosing Disc 4 1 Dosing Disc Size (mm) 7 (Fixed) 19.5 Tamping Pin 1 29 Setting 2 2 11 3 3 13 4 2 14 5 2 16

For both batches, sticking to pin tips was observed. For the 1 mg lot,the sticking was correlated to the hard tamping (pins maxed, maximumtamping).

Good fill weight and content uniformity (CU) results (Table 33) wereobtained except for the end samples. This poor CU was attributed to thesmall batch size rather than segregation, as there was insufficientpowder in the feed frame towards the end of the run. Stratified CUsamples was tested as the program progresses to confirm this assumption.

TABLE 33 Stratified CU Results of F29-1 and F29-5 F29-1 F29-5 (1 mg), 75mg fill, Size #4 (20 mg), 250 mg fill, Size #1 Beginning Middle EndBeginning End Capsule Capsule Capsule Capsule Capsule Weight % LC Weight% LC Weight % LC Weight % LC Weight % LC Average 108.2 97.5 111.4 102.1112.2 100.1 321.7 99.5 309.6 95.0 STD 1.5 1.2 1.2 1.5 1.4 7.0 2.3 2.013.4 5.8 AV 3.9 4.1 16.9 4.7 17.5 Pass L1 Yes Yes No Yes No USP <905>Uniformity of Dosage Units Acceptance Value (AV) ≤15.0 to passrequirements. STD = standard deviation

Based on the good potency and acceptance value results, the process wasscaled to 2 kg technical batches.

6.27 2 kg Technical Batch Manufacturing Trials

One batch each of 1, 5, and 20 mg capsule strengths (F29-1, F29-3 andF29-5) were manufactured at the 2 kg scale. The formulation compositionfor these batches are shown in Table 34.

The final formulation compositions for FIH are shown in Section 6.28.

TABLE 34 2-kg technical batches of 1 mg, 5 mg, and 20 mg (% w/w)Component F29-1 F29-3 F29-5 Compound 1 1.80 6.73 11.05 MCC (AvicelPH102) 21.65 20.42 19.34 Mannitol (Parteck M200) 64.95 61.25 58.01Fumaric acid 5 SLS 1 Crospovidone (Kollidon CL) 4 Fumed silica (Aerosil200) 0.6 Magnesium Stearate 1 (HyQual VG 2257) Fill weight 75 mg 100 mg250 mg Capsule^(a) Size #4 Size #4 Size #1 ^(a)Capsule = Hard gelatin,white opaque ^(a)Based on free-base. 1.0 mg Compound 1 (free-base) wasequivalent to1.34 mg Compound 1 (citrate salt). Drug substance lotpotency factor for these experiments was (0.725 or 1/1.38).

The process flow diagram for the manufacture of the 2 kg technicalbatches is shown in FIG. 33. The encapsulation parameters for thebatches are listed in Table 35.

A narrative of the process is listed below.

Weigh out each raw material in individual plastic bags.

Load the dispensed API and excipients except for magnesium stearate intothe 8-QT square Bin.

Blend the material for 10 min at 25 rpm.

Charge the Comil with the blended material. Using a 20 mesh Comilscreen, pass the blend through Comil at approximately 2800 rpm (40%speed).

Transfer the material into the blender bin. Blend the material for 15min at 15 rpm.

Pass the dispensed magnesium stearate through a 30 mesh (595 micron)screen directly into screen pan and add to the blender.

Blend the material for 2 minutes at 25 rpm.

Discharge the blend into feeding bowl of Bosch GKF702 Encapsulator.

Set up the Bosch GKF702 Encapsulator with the following Change parts:

a. 75 mg fill, size #4 capsules: 7 mm fixed dosing disk

b. 100 mg fill, size #4 capsules: 12 mm adjustable dosing disk

c. 250 mg fill, size #1 capsules: 19.5 mm adjustable dosing disk

Set encapsulation speed at 90 cycles per minute. Start encapsulation andadjust the machine to provide target weight.

Collect capsules as they are discharged from the Encapsulator on asuitable sieve. As the capsules fill the sieve, use the vacuum tode-dust the capsules. Place the capsules into the tared doublepolyethylene bag lined container.

Package the bulk capsules in the bag container into 100 cc HDPE bottles(7 count per bottle, heat induction sealed).

TABLE 35 Encapsulation Setup Parameters Parameter F29-1 (1 mg) F29-3(5mg) F29-5 (20 mg) Dosing Disc 4 4 1 Dosing Disc Size (mm) 7 12 19.5Machine Speed 90 90 90 (cycles/min) Tamping Pin 1 2 4 9 Setting 2 2 5 103 2 4 11 4 2 5 14 5 2 9 17

For all batches, drug substance sticking to pin tips was observed. Forthe 1 mg lot, the tamping pins were set at maximum.

Bulk and tap densities and flow properties for the 2 kg technicalbatches are listed in Table 36. Flow property scales for Carr's(Compressibility) Index and Hausner's Ratio are described in Table 37.The flow of the blends was assessed as very poor to passible.

TABLE 36 Bulk and Tap Density and Flow Properties for the TechnicalBatches Property F29-1 (1 mg) F29-3 (5 mg) F29-5 (20 mg) Bulk Density(g/mL) 0.4672 0.4363 0.4229 Tapped Density (g/mL) 0.6088 0.6371 0.6278Hausner' s Ratio 1.30 1.46 1.48 Carr's Index 23.3 31.5 32.6 Carr's(Compressibility) Index = (tapped density − bulk density)*100/tappeddensity Hausner's Ratio = tapped density/bulk density

TABLE 37 Generally Accepted Scales of Flow Properties Flow CharacterCarr's (Compressibility) Index (%) Hausner's Ratio Excellent ≤101.00-1.11 Good 11-15 1.12-1.18 Fair 16-20 1.19-1.25 Passible 21-251.26-1.34 Poor 26-31 1.35-1.45 Very Poor 32-37 1.46-1.59 Very, Very Poor≥38 ≥1.60 Carr's (Compressibility) Index = (tapped density- bulkdensity)*100/tapped density Hausner's Ratio = tapped density/bulkdensity

FFC was assessed by ring shear, and the blends were assessed as havinggood flow properties (Table 38).

TABLE 38 Flowability Measurement by Ring Shear FFC F29-1 F29-3 F29-5Test 1 15.48 10.2  6.17 Test 2 20.78 11.02 6.22 Test 3 20.56 Average18.94 10.61 6.19 FFC = Flow function coefficients

FFC values greater than 5 had good flow properties, and all threebatches had FFC>5.

The particle size distribution of the formulations was assessed usingscreens, and the results are listed in Table 39.

TABLE 39 Particle size distribution by sieve analysis Parameter PD01-282PD01-283 PD01-284 Sample weight (g) 5.042 5.025 5.0042 Shake Time (min)5 5 5 Screen Amplitude 3 5 3 420 μm Mesh #40 1.4 2.1 2.4 250 μm Mesh #6012.7 13.0 12.5 177 μm Mesh #80 16.6 17.1 17.4 149 μm Mesh #100 11.9 11.712.8 125 μm Mesh #120 13.3 13.2 13.0  74 μm Mesh #200 29.2 25.4 26.6 0pan 14.9 17.6 15.3 Average particle size (μm) 122.6 123.8 126.8

Stratified CU was tested, and acceptable results were obtained for beg,mid, and end samples as listed in Table 40, Table 41, and Table 42.

TABLE 40 Content Uniformity and Weight Variability PD01-282 (1 mg)Beginning Middle End Sample % LC Weight Sample % LC Weight Sample % LCWeight 1 93.7 108.3 1 91.1 107.8 1 95.4 110.4 2 92.7 109.8 2 94.3 111.02 99.7 112.3 3 93.9 110.3 3 91.6 108.4 3 93.9 110.5 4 90.7 109.6 4 93.6111.4 4 98.2 112.6 5 92.2 110.0 5 95.5 110.8 5 98.4 112.9 6 93.7 109.0 692.6 108.3 6 96.4 111.7 7 93.1 108.7 7 93.7 110.9 7 96.3 112.1 8 91.7107.2 8 94.5 110.7 8 95.3 111.8 9 90.8 109.2 9 90.5 107.2 9 98.8 113.010 90.0 108.9 10 94.0 109.2 10 97.4 111.9 Average 92.2 109.1 Average93.1 109.6 Average 97.0 111.9 SD 1.4 0.9 SD 1.6 1.6 SD 1.8 0.9 % RSD 1.50.8 % RSD 1.7 1.4 % RSD 1.9 0.8 AV 9.6 AV 9.2 AV 5.9 AV = acceptancevalue; LC = label claim; SD = standard deviation. RSD = relativestandard deviation

TABLE 41 Content Uniformity and Weight Variability F3 (5 mg) BeginningMiddle End Sample % LC Weight Sample % LC Weight Sample % LC Weight 194.4 136.4 1 95.4 134.98 1 97.2 136.3 2 95.3 135.8 2 97.7 137.64 2 99.5140.8 3 97.3 138.1 3 95.3 134.45 3 99.1 139.8 4 101.3 142.2 4 97.2137.47 4 99.4 139.2 5 97.6 138.9 5 95.4 134.64 5 98.1 138.3 6 94.3 134.16 102.0 142.2 6 104.5 141.7 7 97.5 136.5 7 96.4 136.81 7 98.3 138.1 897.1 138.6 8 95.9 134.53 8 98.9 137.9 9 97.4 138.1 9 97.8 136.71 9 100.0138.0 10 97.6 138.2 10 98.5 138.15 10 99.5 139.1 Average 97.0 137.7Average 97.2 136.8 Average 99.5 138.9 SD 2.0 2.2 SD 2.0 2.4 SD 1.9 1.6 %RSD 2.1 1.6 % RSD 2.1 1.7 % RSD 1.9 1.1 AV 6.4 AV 6.2 AV 4.7 AV =acceptance value; LC = label claim; SD = standard deviation; RSD =relative standard deviation

TABLE 42 Content Uniformity and Weight Variability F5 (20 mg) BeginningMiddle End Sample % LC Weight Sample % LC Weight Sample % LC Weight 198.7 327.5 1 94.0 319.63 1 97.0 317.4 2 98.5 328.4 2 95.4 325.48 2 99.1321.8 3 96.3 322.2 3 98.9 331.33 3 99.3 321.6 4 96.9 326.3 4 99.2 330.394 98.1 318.0 5 93.9 317.8 5 97.9 328.89 5 101.5 327.2 6 98.2 330.0 694.3 318.8 6 93.0 307.0 7 96.8 326.0 7 94.3 317.63 7 97.9 320.3 8 96.8321.6 8 96.0 321.43 8 97.8 317.9 9 91.8 310.8 9 97.2 327.27 9 98.3 319.510 94.9 320.8 10 94.2 327.76 10 96.8 316.5 Average 96.3 323.1 Average96.1 324.9 Average 97.9 318.7 SD 2.2 5.8 SD 2.0 5.1 SD 2.2 5.1 % RSD 2.31.8 % RSD 2.1 1.6 % RSD 2.2 1.6 AV 7.5 AV 7.2 AV 5.8 AV = acceptancevalue; LC = label claim; SD = standard deviation; RSD = relativestandard deviation

The 3 technical batches have been set up on a formal (ICH) stabilityprogram to support the clinical program.

6.28 FIH Formulation Composition

In review of the data, and taking into consideration stability,dissolution performance, and manufacturability, the enhanced formulation(contain fumaric acid and sodium lauryl sulfate) in gelatin capsuleshells was selected for the FIH study. Formulation compositions of thethree strengths are listed in Table 43.

TABLE 43 FIH Formulation Composition Formulation Composition 1 mg^(a) 5mg^(a) 20 mg^(a) Component mg/cap w/w % mg/cap w/w % mg/cap w/w %Compound 1 1.34 1.79 6.70 6.70 26.80 10.72 Avicel PH102 16.24 21.6520.42 20.42 48.53 19.41 Mannitol 48.72 64.96 61.28 61.28 145.68 58.27(Parteck M200) Sodium 0.75 1.0 1.00 1.0 2.50 1.0 lauryl sulfate Fumaricacid 3.75 5.0 5.00 5.0 12.50 5.0 Crospovidone 3.00 4.0 4.00 4.0 10.004.0 Aerosil 200 0.45 0.6 0.60 0.6 1.50 0.6 Magnesium 0.75 1.0 1.00 1.02.50 1.0 Stearate Fill weight 75.00 100.0 100.00 100.0 250.00 100.0Capsule Shell^(b) Size #4 Size #4 Size #1 ^(a)Based on free-base. 1.0 mgCompound 1 (free-base) is equivalent to 1.34 mg Compound 1 (citratesalt). Actual drug substance weight was based upon the drug substancelot potency factor, with adjustments in weight made to mannitol toobtain the target blend weight. ^(b)Capsule = Hard gelatin, whiteopaque.

6.29 Conclusions

Blend in capsule formulation development was undertaken to minimize thepH dependence on the in vitro dissolution drug release. 1, 5, and 20 mgformulations were developed for FIH clinical trials based on dog PK, invitro dissolution, manufacturability, and stability studies. Theenhanced formulations contained an acidifier (fumaric acid) andsurfactant (sodium lauryl sulfate) for control of local pH and enhancingdrug solubility. This combination of excipients, leading to the enhancedformulation, reduced the variability in dissolution release profileobserved with the conventional formulation in various pH media.

A dry blending process was developed for all strengths. The formulationshave been successfully scaled to 2 kg. Acceptable CU was demonstratedfor 2-kg batch size. The same process was expected to be techtransferred to a contract manufacturing organization for themanufacturing of 3-kg engineering and clinical trial material (CTM)batches.

6.30 Capsules A-J

Capsules A-H were produced and examined in the below studies. Thecomposition of each capsule is provided in Table 44.

TABLE 44 Composition of Capsules Capsule A B C D E F G H ComponentPercent by weight Compound 1  37%  25%  25%  50%  50%  50%  50%  50%HPMC  53% — —  40% — —  50% — PVA-P —  65% — —  40% — —  50% PVP VA 64 ——  65% — —  40% — — TPGS  10%  10%  10%  10%  10%  10% — — Total 100%100% 100% 100% 100% 100% 100% 100%

FIG. 34 shows dissolution profiles of Compound 1 formulations inintestinal buffer dissolution over 90 minutes.

FIG. 35 shows dissolution profiles of Compound 1 formulations inintestinal buffer dissolution and speciation. Capsule E shows the bestperformance with regards to total solubilized drug. The higher loadingPVA-P formulations showed better performance compared to their lowerloading counterparts. The addition of TPGS to the formulation showed apositive impact on the solubility of Compound 1.

FIG. 36 shows a dissolution comparison across the PVA-P formulations(Capsule B, Capsule E, and Capsule H). The PVA-P formulations performedbetter at higher loading, as well as with the addition of TPGS.

FIG. 37 showed a dissolution comparison across the PVP VA64 formulations(Capsule C and Capsule F). Increased loading and the addition of TPGSshowed only a modest improvement on formulations with PVP VA64 comparedto other polymers.

FIG. 38 shows a dissolution comparison across the HPMC formulations(Capsule A, Capsule D, and Capsule G). Increasing the drug loading withHPMC had little impact on dissolution performance. TPGS showed asignificant improvement in the solubility of Compound 1 in Capsule A.

FIG. 39 shows the glass transition temperature versus relative humidity.

FIG. 40 shows the reversible and nonversible heat flow of Capsule A andCapsule H at less then 5% relative humidity.

FIG. 41 shows the reversible and nonversible heat flow of Capsule A andCapsule H at 75% relative humidity.

FIG. 42 shows the reversible and nonversible heat flow of Capsule G andCapsule E at less than 5% relative humidity.

FIG. 43 shows the reversible and nonversible heat flow of Capsule G andCapsule E at 75% relative humidity.

FIG. 44 shows the suspension stability of Capsule A in Methocel.

FIG. 45 shows the suspension stability of Capsule H in Methocel.

FIG. 46 shows the suspension stability of Capsule G in Methocel.

FIG. 47 shows the suspension stability of Capsule E in Methocel.

FIG. 48 shows the suspension stability, as visualized by PLM, of CapsuleA in Methocel.

FIG. 49 shows the suspension stability, as visualized by PLM, of CapsuleH in Methocel.

FIG. 50 shows the suspension stability, as visualized by PLM, of CapsuleG in Methocel.

FIG. 51 shows the suspension stability, as visualized by PLM, of CapsuleE in Methocel.

6.31 Mouse in vivo Pharmacokinetic Study

TABLE 45 mTOR + CD-1 Male Mouse Oral Dosing Pharmacokinetic ParametersCD-1 Male Mouse PK Mean Value¹ Mean ± SD (N = 4) Parameters Capsule GCapsule E Capsule A Capsule H Capsule I² Capsule J³ Cmax (μM) 1.16 0.9020.703 0.612 0.464 ± 0.182  1.42 ± 0.549 Tmax (hr) 0.25 0.25 0.25 0.500.50 ± 0.00 0.50 ± 0.00 AUC_((0-inf)) 1.12 1.00 1.36 1.41 1.24 ± 0.242.49 ± 0.68 (μM · hr) F % 8.6 7.7 10 11 10 19 ¹Data obtained vianon-serial sampling from two groups with n = 4 per group. ²Capsule Icomprises .5% HPMC/1% TPGS. ³Capsule J comprises CMC/Tween.

This study evaluated the effect of two Spayed-dried dispersion (SDD)formulations Capsule G, Capsule E, Capsule A, and Capsule Hon oralexposure of Compound 1 in male CD-1 mice at 10 mg/kg. The SDDformulations had 5000 loading of Compound 1. The overall exposure wascomparable between the two DSS formulations. The exposure data was alsosimilar to those from the other three tested formulations. Overall, alltested formulations did not improve exposure of Compound 1 in CD-1 miceat 10 mg/kg compared to the standard formulation in CMC/Tween. Theresults were as expected since solubility/dissolution of this compoundwas not the major limiting factor to exposure at low dose levels.

Table 46 shows the plasma concentration profile results following asingle oral administration of Capsule Gin male CD-1 mice.

TABLE 46 Capsule G: Tabular Summary of Plasma Concentration (μM) PlasmaConcentration of Compound 1 (μM) Time (hr) Mouse 1/9 Mouse 2/10 Mouse3/11 Mouse 4/12 Mean SD 0 0.00 0.00 0.0 0.00 0.0 0.0 0.25 0.891 0.9752.42 0.364 1.162 0.881 0.5 0.990 0.230 0.533 0.413 0.541 0.324 1 0.2240.265 0.657 0.062 0.302 0.252 2 0.179 0.145 0.072 0.163 0.140 0.048 40.0156 0.0538 0.0387 0.0065 0.0287 0.0216 6 BLQ 0.0189 0.0340 0.03560.0221 0.0166 8 0.035 0.0270 0.0113 0.0104 0.0209 0.0121 24 BLQ BLQ BLQBLQ BLQ NC BLQ: below the limit of quantitation; NC: not calculable.

FIG. 52 shows the plasma concentration profile results following asingle oral administration of Capsule Gin male CD-1 mice.

Table 47 shows the plasma concentration profile results following asingle oral administration of Capsule E in male CD-1 mice.

TABLE 47 Capsule E: Tabular Summary of Plasma Concentration (μM) PlasmaConcentration of Compound 1 (μM) Time Mouse Mouse Mouse Mouse (hr) 1/92/10 3/11 4/12 Mean SD 0 0 0.0 0.00 0 0 0 0.25 0.570 0.601 1.622 0.8170.902 0.492 0.5 0.293 0.978 0.539 0.277 0.522 0.327 1.0 0.273 0.2250.248 0.178 0.231 0.040 2 0.118 0.189 0.250 0.124 0.170 0.062 4 0.04200.0255 0.023 0.0361 0.0317 0.0089 6 0.0341 BLQ 0.0243 0.0217 0.02000.0144 8 0.0109 0.0110 0.0106 0.0102 0.0107 0.0004 24 BLQ BLQ 0.00126BLQ BLQ NC BLQ: below the limit of quantitation; NC: not calculable;values in italics are estimated.

FIG. 53 shows the plasma concentration profile results following asingle oral administration of Capsule E in male CD-1 mice.

Table 48 shows the plasma concentration profile results following asingle oral administration of Capsule 1 in male CD-1 mice.

TABLE 48 Capsule I: Tabular Summary of Plasma Concentration (μM) PlasmaConcentration of Compound 1 (μM) Time (hr) Mouse 1 Mouse 2 Mouse 3 Mouse4 Mean SD 0 0 0 0 0 0 0 0.5 0.357 0.377 0.736 0.385 0.464 0.182 1.50.150 0.092 0.223 0.191 0.164 0.056 3 0.125 0.0717 0.0926 0.171 0.1150.043 5 0.0795 0.0568 0.0388 0.1042 0.0698 0.0283 8 0.0710 0.0326 0.06140.0365 0.0504 0.0187

FIG. 54 shows the plasma concentration profile results following singleoral administration of Capsule I in male CD-1 mice.

Table 49 shows the plasma concentration profile results following asingle oral administration of Capsule J in male CD-1 mice.

TABLE 49 Capsule J: Tabular Summary of Plasma Concentration (μM) PlasmaConcentration of Compound 1 (μM) Time (hr) Mouse 1/9 Mouse 2/10 Mouse3/11 Mouse 4* Mean SD 0 0 0 0 0 0 0 0.5 0.845 1.46 1.94 3.54 1.42 0.551.5 0.275 0.702 0.578 0.962 0.519 0.220 3 0.285 0.301 0.192 1.85 0.2590.059 5 0.0500 0.0653 0.0702 0.292 0.0618 0.0105 8 0.0259 0.0621 0.03410.0372 0.0407 0.0190 *Mouse 4 is an outlier based on Grubb's test, andtherefore excluded for data analysis.

FIG. 55 shows the plasma concentration profile results following asingle oral administration of Capsule J in male CD-1 mice.

FIG. 56 shows a comparison of the concentration profile resultsfollowing a single oral administration of Capsule G, Capsule E, CapsuleI, and Capsule J.

6.32 Tablets

Tablets A-C were produced and examined in the below studies.

Table 50 shows the composition of Tablet A.

TABLE 50 Composition of Tablet A Composition Amount Ingredient (% w/w)(mg per tablet) Compound 1 20 50 Microcrystalline 37.25 93.125 cellulose(Avicel PH102) EMPROVE ® 37.25 93.125 Parteck ® Ac-Di-Sol ® 4 10AEROSIL ® 200 0.5 1.25 Magnesium 1 2.5 stearate Total 100 250

Table 51 shows the composition of Tablet B.

TABLE 51 Composition of Tablet B Composition Amount Ingredient (% w/w)(mg per tablet) HCl Salt of 20 50 Compound 1 Microcrystalline 37.2593.125 cellulose (Avicel PH102) EMPROVE ® 37.25 93.125 Parteck ®Ac-Di-Sol ® 4 10 AEROSIL ® 200 0.5 1.25 Magnesium 1 2.5 stearate Total100 250

Table 52 shows the composition of Tablet C.

TABLE 52 Composition of Tablet C Composition Amount Ingredient (% w/w)(mg per tablet) Citrate Salt of 20 50 Compound 1 Microcrystalline 37.2593.125 cellulose (Avicel PH102) EMPROVE ® 37.25 93.125 Parteck ®Ac-Di-Sol ® 4 10 AEROSIL ® 200 0.5 1.25 Magnesium 1 2.5 stearate Total100 250

FIG. 57 shows the dissolution of Tablet A, Tablet B, and Tablet C in pH2 phosphate buffer.

FIG. 58 shows the dissolution of Tablet A (middle curve), Tablet B (topcurve), and Tablet C (bottom curve) in pH 5 phosphate buffer and 0.1%sodium laureth sulfate. The HCl salt of Compound 1 had a higherdissolution than the free base of Compound 1 and the citrate salt ofCompound 1.

6.33 Example 4: Formulation and Stability Study

Solubility Study: Compound 1 free base pKa was determined to be 5.14.Therefore, solubility of Compound 1 is pH dependent: 0.003 mg/ml inwater (pH 8.1), 3.5 mg/ml in simulated gastric fluids (SGF) (pH 1.9),0.002 mg/ml in the simulated intestinal fluids (SIF) (pH 7.3).Solubility in the preclinical formulation, 0.5% CMC/0.25% Tween 80, wasdetermined to be 0.18 mg/ml at pH 8.1. Solubilities of Compound 1 in SGFand SIF under the fasted and fed conditions are listed in Table 53.

TABLE 53 Solubility of Compound 1 Freebase Monohydrate in Bio-relevantMedia at 24 Hours Vehicles Concentration (mg/mL) pH @ 24 hr FaSSIF 0.266.48 FeSSIF 2.07 4.94 FaSSGF 2.81 1.84 FeSSGF 0.004 6.31

Chemical Stability Study:Solid state stability of Compound 1 free basemonohydrate was evaluated at 80° C. for 2 weeks and 40° C./75% RH, 50°C./75% RH and 60° C. for up to 5 weeks. The results indicated thatCompound 1 free base monohydrate is chemically relatively stable underall storage conditions and durations.

Physical Stability Study: The free base monohydrate lost water andconverted to a dehydrate form after being heated at 60 and 80° C. Thisdehydrate form converted back to monohydrate immediately when sampleswere exposed to room temperature and RH>30%. If RH is in the range of5-30%, the dehydrate form may take 1-3 days to convert back tomonohydrate.

6.34 Solution Stability Study:

The solution stability of Compound 1 free base in water, SGF (pH 1.3),SIF (pH 7.5), and 0.1N NaOH with and without light protection at 37° C.was tested. The results showed that Compound 1 free base is relativelystable (>95% remaining) in all vehicles for 4 days except for the samplein 0.1N NaOH without light protection. Significant degradation wasobserved for this sample, only 88% remaining at day 1 and 61% remainingat day 4.

No significant degradation was observed for a 6 mg/mL suspensionformulation in 0.5% CMC and 0.25% Tween 80, stored at ambienttemperature and 2-8° C. for 7 days.

6.35 Formulation Development

Free Base Monohydrate

To assess the feasibility of using Compound 1 in a capsule to supportFIH study, a dissolution study with a capsule containing 125 mg Compound1 free base monohydrate was performed in the media of 0.01N HCl and0.001N HCl at 37° C. Capsule shell shrinkage was observed. About 80%Compound 1 was released in 0.01N HCl and only 10% in 0.001N HCl at 60minutes, suggesting that dissolution of Compound 1 free base monohydratewas highly pH dependent and developing a AIC formulation for freebasemonohydrate to support FIH study may be challenging. Blend in capsule orother formulation approaches may be necessary.

Citrate Salt

A dissolution study for citrate salt in a capsule in 0.01N HCl was alsocarried out. The results as provided in FIG. 59 showed that citrate salthad a better dissolution profile compared to freebase monohydratesuggesting AIC formulation approach to support FIH may be feasible forcitrate salt.

1-20. (canceled)
 21. A method for achieving a Response EvaluationCriteria in Solid Tumors (RECIST 1.1) of complete response, partialresponse or stable disease in a patient having a solid tumor, comprisingadministering to the patient an effective amount of a formulation,wherein the formulation is a capsule comprisingcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof in an amount that is 30-40%of the capsule by weight, an excipient in an amount that is 50-60% ofthe capsule by weight, and tocophersolan in an amount that is 5-15% ofthe capsule by weight, a capsule comprising 60-70%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 20-30% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising 45-55%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 35-45% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising a citrate salt ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamidein an amount that is 0.5-20% of the capsule weight, and sodium laurylsulfate, or a tablet comprising 15-25% ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor an isotopologue, pharmaceutically acceptable salt, tautomer, solvate,hydrate, co crystal, clathrate, or polymorph thereof by weight, 32-43%of microcrystalline cellulose by weight, 32-43% of mannitol by weight,2-6% of croscarmellose sodium by weight, 0.3-0.7% of fumed silica byweight, and 0.5-1.5% magnesium stearate by weight.
 22. The method ofclaim 21, wherein the solid tumor is melanoma, colorectal cancer,stomach cancer, head and neck cancer, thyroid cancer, bladder cancer,CNS cancer, lung cancer, pancreatic cancer, or soft tissue cancer. 23.The method of claim 21, wherein the solid tumor is bladder cancer,breast cancer, CNS cancer, colon cancer, gastrointestinal cancer,endocrine cancer, female genitoureal cancer, head and neck cancer,hematopoietic cancer, kidney cancer, liver cancer, lung cancer,melanoma, pancreas cancer, prostate cancer, or soft tissue cancer. 24.The method of claim 21, wherein the solid tumor is glioma,neuroblastoma, stomach cancer, thyroid cancer, adrenal gland cancer,cancer of the uterus, cervix, ovary clear cell, or vulva, leukemia,myeloma, non-small cell lung cancer (NSCLC), small cell lung cancer(SCLC), sarcoma or osteosarcoma.
 25. The method of claim 21, wherein thesolid tumor is hepatocellular carcinoma (HCC).
 26. The method of claim21, wherein the solid tumor is colorectal cancer (CRC), melanoma,gastric cancer, hepatocellular carcinoma, lung cancer, pancreaticcancer, leukemia, multiple myeloma, stomach cancer or sarcoma.
 27. Amethod for achieving complete remission, partial remission or stabledisease, as determined by the International Workshop Criteria (IWC) forNHL in a patient having a cancer, comprising administering to thepatient an effective amount of a formulation, wherein the formulation isa capsule comprisingcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof in an amount that is 30-40%of the capsule by weight, an excipient in an amount that is 50-60% ofthe capsule by weight, and tocophersolan in an amount that is 5-15% ofthe capsule by weight, a capsule comprising 60-70%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 20-30% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising 45-55%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 35-45% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising a citrate salt ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamidein an amount that is 0.5-20% of the capsule weight, and sodium laurylsulfate, or a tablet comprising 15-25% ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor an isotopologue, pharmaceutically acceptable salt, tautomer, solvate,hydrate, co crystal, clathrate, or polymorph thereof by weight, 32-43%of microcrystalline cellulose by weight, 32-43% of mannitol by weight,2-6% of croscarmellose sodium by weight, 0.3-0.7% of fumed silica byweight, and 0.5-1.5% magnesium stearate by weight.
 28. The method ofclaim 26, wherein the cancer is melanoma, colorectal cancer, stomachcancer, head and neck cancer, thyroid cancer, bladder cancer, CNScancer, lung cancer, pancreatic cancer, or soft tissue cancer.
 29. Themethod of claim 26, wherein the cancer is bladder cancer, breast cancer,CNS cancer, colon cancer, gastrointestinal cancer, endocrine cancer,female genitoureal cancer, head and neck cancer, hematopoietic cancer,kidney cancer, liver cancer, lung cancer, melanoma, pancreas cancer,prostate cancer, or soft tissue cancer.
 30. The method of claim 26,wherein the cancer is glioma, neuroblastoma, stomach cancer, thyroidcancer, adrenal gland cancer, cancer of the uterus, cervix, ovary clearcell, or vulva, leukemia, myeloma, non-small cell lung cancer (NSCLC),small cell lung cancer (SCLC), sarcoma or osteosarcoma.
 31. The methodof claim 26, wherein the cancer is hepatocellular carcinoma (HCC). 32.The method of claim 26, wherein the cancer is colorectal cancer (CRC),melanoma, gastric cancer, hepatocellular carcinoma, lung cancer,pancreatic cancer, leukemia, multiple myeloma, stomach cancer orsarcoma.
 33. A method for achieving a stringent complete response,complete response, very good partial response, or partial response, asdetermined by the International Uniform Response Criteria for MultipleMyeloma (IURC) in a patient having multiple myeloma, comprisingadministering to the patient an effective amount of a formulation,wherein the formulation is a capsule comprisingcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof in an amount that is 30-40%of the capsule by weight, an excipient in an amount that is 50-60% ofthe capsule by weight, and tocophersolan in an amount that is 5-15% ofthe capsule by weight, a capsule comprising 60-70%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 20-30% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising 45-55%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 35-45% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising a citrate salt ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamidein an amount that is 0.5-20% of the capsule weight, and sodium laurylsulfate, or a tablet comprising 15-25% ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor an isotopologue, pharmaceutically acceptable salt, tautomer, solvate,hydrate, co crystal, clathrate, or polymorph thereof by weight, 32-43%of microcrystalline cellulose by weight, 32-43% of mannitol by weight,2-6% of croscarmellose sodium by weight, 0.3-0.7% of fumed silica byweight, and 0.5-1.5% magnesium stearate by weight.
 34. A method forinducing a therapeutic response assessed with the Response Assessmentfor Neuro-Oncology (RANO) Working Group for glioblastoma multiforme(GBM) in a patient having GBM, comprising administering to the patientan effective amount of a formulation, wherein the formulation is acapsule comprisingcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof in an amount that is 30-40%of the capsule by weight, an excipient in an amount that is 50-60% ofthe capsule by weight, and tocophersolan in an amount that is 5-15% ofthe capsule by weight, a capsule comprising 60-70%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 20-30% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising 45-55%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 35-45% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising a citrate salt ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamidein an amount that is 0.5-20% of the capsule weight, and sodium laurylsulfate, or a tablet comprising 15-25% ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor an isotopologue, pharmaceutically acceptable salt, tautomer, solvate,hydrate, co crystal, clathrate, or polymorph thereof by weight, 32-43%of microcrystalline cellulose by weight, 32-43% of mannitol by weight,2-6% of croscarmellose sodium by weight, 0.3-0.7% of fumed silica byweight, and 0.5-1.5% magnesium stearate by weight.
 35. The method ofclaim 34, wherein the cancer is melanoma, colorectal cancer, stomachcancer, head and neck cancer, thyroid cancer, bladder cancer, CNScancer, lung cancer, pancreatic cancer, or soft tissue cancer.
 36. Themethod of claim 34, wherein the cancer is bladder cancer, breast cancer,CNS cancer, colon cancer, gastrointestinal cancer, endocrine cancer,female genitoureal cancer, head and neck cancer, hematopoietic cancer,kidney cancer, liver cancer, lung cancer, melanoma, pancreas cancer,prostate cancer, or soft tissue cancer.
 37. The method of claim 34,wherein the cancer is glioma, neuroblastoma, stomach cancer, thyroidcancer, adrenal gland cancer, cancer of the uterus, cervix, ovary clearcell, or vulva, leukemia, myeloma, non-small cell lung cancer (NSCLC),small cell lung cancer (SCLC), sarcoma or osteosarcoma.
 38. The methodof claim 34, wherein the cancer is hepatocellular carcinoma (HCC). 39.The method of claim 34, wherein the cancer is colorectal cancer (CRC),melanoma, gastric cancer, hepatocellular carcinoma, lung cancer,pancreatic cancer, leukemia, multiple myeloma, stomach cancer orsarcoma.
 40. A method for improving the Eastern Cooperative OncologyGroup Performance Status (ECOG) of a patient having a cancer, comprisingadministering to the patient an effective amount of a formulation,wherein the formulation is a capsule comprisingcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof in an amount that is 30-40%of the capsule by weight, an excipient in an amount that is 50-60% ofthe capsule by weight, and tocophersolan in an amount that is 5-15% ofthe capsule by weight, a capsule comprising 60-70%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 20-30% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising 45-55%cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide,or a pharmaceutically acceptable salt, tautomer, solvate, hydrate,co-crystal, clathrate, or polymorph thereof by weight, 35-45% of anexcipient by weight, and 5-15% of tocophersolan by weight, a capsulecomprising a citrate salt ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamidein an amount that is 0.5-20% of the capsule weight, and sodium laurylsulfate, or a tablet comprising 15-25% ofcis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamideor an isotopologue, pharmaceutically acceptable salt, tautomer, solvate,hydrate, co crystal, clathrate, or polymorph thereof by weight, 32-43%of microcrystalline cellulose by weight, 32-43% of mannitol by weight,2-6% of croscarmellose sodium by weight, 0.3-0.7% of fumed silica byweight, and 0.5-1.5% magnesium stearate by weight.
 41. The method ofclaim 39, wherein the cancer is melanoma, colorectal cancer, stomachcancer, head and neck cancer, thyroid cancer, bladder cancer, CNScancer, lung cancer, pancreatic cancer, or soft tissue cancer.
 42. Themethod of claim 39, wherein the cancer is bladder cancer, breast cancer,CNS cancer, colon cancer, gastrointestinal cancer, endocrine cancer,female genitoureal cancer, head and neck cancer, hematopoietic cancer,kidney cancer, liver cancer, lung cancer, melanoma, pancreas cancer,prostate cancer, or soft tissue cancer.
 43. The method of claim 39,wherein the cancer is glioma, neuroblastoma, stomach cancer, thyroidcancer, adrenal gland cancer, cancer of the uterus, cervix, ovary clearcell, or vulva, leukemia, myeloma, non-small cell lung cancer (NSCLC),small cell lung cancer (SCLC), sarcoma or osteosarcoma.
 44. The methodof claim 39, wherein the cancer is hepatocellular carcinoma (HCC). 45.The method of claim 39, wherein the cancer is colorectal cancer (CRC),melanoma, gastric cancer, hepatocellular carcinoma, lung cancer,pancreatic cancer, leukemia, multiple myeloma, stomach cancer orsarcoma.